Methods of treating cancer with mTOR inhibitors

Abstract

The present disclosure relates to methods of treating a disease or disorder (e.g., cancer) with an mTOR inhibitor. In particular, the present disclosure relates to methods of treating a subject having cancer by administering specific doses of an mTOR inhibitor. In some embodiments, the present disclosure includes methods for delaying, preventing, or treating acquired resistance to a RAS inhibitor using a dose of an mTOR inhibitor. In some embodiments, the present disclosure relates to methods of using tacrolimus to treat or prevent adverse events associated with the administration of an mTOR inhibitor.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 348,263 filed on June 2, 2022 and U.S. Provisional Application Serial No. 63 / 345,809 filed on May 25, 2022, which are incorporated herein by reference in their entirety for all purposes. Reference to a sequence listing

[0002] The contents of the electronic sequence listing (REME_032_02WO_SeqList_ST26.xml; size: 17,326 bytes; creation date: May 22, 2023) are incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to methods of treating a disease or disorder (e.g., cancer) with an mTOR inhibitor. In particular, in some embodiments, the present disclosure relates to methods of treating a subject with cancer by administering a dose of an mTOR inhibitor. In some embodiments, the present disclosure includes methods for delaying, preventing, or treating acquired resistance to RAS inhibitors using a dose of an mTOR inhibitor. In some embodiments, the present disclosure relates to methods of using tacrolimus to treat or prevent adverse events associated with the administration of an mTOR inhibitor. Background Art

[0004] The mammalian target of rapamycin (mTOR) is a serine-threonine kinase related to the phosphoinositide 3-kinase (PI3K) family of lipid kinases. mTOR exists in two complexes (mTORC1 and mTORC2) that are differentially regulated, have different substrate specificities, and are differentially sensitive to rapamycin. mTORC1 integrates signals from growth factor receptors with cellular nutrient status and controls the level of cap-dependent mRNA translation by regulating the activity of key translation components such as cap-binding proteins and the oncogene eIF4E.

[0005] First generation mTOR inhibitors and pan- and isoform-selective PI3K inhibitors have been evaluated for the treatment of cancers that rely on activation of PI3K / mTOR signaling. Rapamycin analogs and pan-mTOR active site inhibitors do not completely inhibit mTORC1-mediated 4EBP1 phosphorylation at clinically achievable exposures, and can therefore be considered "incomplete" pathway inhibitors. This is believed to be consistent, at least in part, with the minimal clinical success of these agents. In addition, pan-mTOR active site inhibitors exhibit a lack of selectivity and may inhibit lipid kinases. There is a large class of cancers that have dysregulation of PI3K / mTOR signaling, and unmet medical needs that are currently not addressed by existing inhibitor treatment strategies.

[0006] Currently, most subjects with mutations / rearrangements that confer mTOR pathway activation do not have approved targeted therapy options. This represents a subject population that can potentially benefit from treatment. In addition, resistance to currently approved and emerging targeted therapies provides another potential subject population. Treatment options for both subject populations mainly include chemotherapy regimens, which provide modest benefits and are often associated with harmful side effects. Therefore, new treatment options are needed for these subjects. Summary of the invention

[0007] The present disclosure relates to methods for treating a disease or disorder (e.g., cancer) with an mTOR inhibitor (e.g., RMC-5552). In particular, the present disclosure provides methods comprising administering a specific dose of an mTOR inhibitor (e.g., RMC-5552). It has been unexpectedly found that such methods are both effective and tolerable to the subject.

[0008] The present disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject a compound at a dose of about 3 mg / week to about 25 mg / week; The compound is RMC-5552: or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0009] The present disclosure also provides a method of treating a subject having salivary gland cancer, the method comprising administering to the subject a compound at a dose of about 3 mg / week to about 25 mg / week; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0010] The present disclosure also provides a method for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg / week to about 25 mg / week of a compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0011] The present disclosure also provides a method of treating acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg / week to about 25 mg / week of a compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0012] The present disclosure also provides for the use of a compound in treating cancer, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0013] The present disclosure also provides for the use of a compound in the manufacture of a medicament for treating cancer, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0014] The present disclosure also provides a compound for use in a method of treating cancer, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0015] The present disclosure also provides an agent for treating cancer, the agent comprising a compound, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0016] The present disclosure also provides a compound for use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to the subject a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0017] The present disclosure also provides a combination of a compound and a RAS inhibitor for simultaneous, separate or sequential use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0018] The present disclosure also provides for the use of a compound in a treatment for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the treatment comprising administering to the subject from about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0019] The present disclosure also provides for the use of a compound in the manufacture of a medicament for the treatment of delaying or preventing acquired resistance to a RAS inhibitor, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0020] The present disclosure also provides a compound for use in a method of delaying or preventing acquired resistance to a RAS inhibitor, the method comprising administering a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0021] The present disclosure also provides an agent for the treatment of delaying or preventing acquired resistance to a RAS inhibitor, the agent comprising a compound, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0022] The present disclosure also provides for the use of a compound in treating acquired resistance to a RAS inhibitor, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0023] The present disclosure also provides for the use of a compound in the manufacture of a medicament for treating acquired resistance to RAS inhibitors, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0024] The present disclosure also provides a compound for use in a method of treating acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0025] The present disclosure also provides an agent for treating acquired resistance to RAS inhibitors, the agent comprising a compound, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof; The compound is RMC-5552 or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any one of the foregoing.

[0026] The present disclosure also provides a method of treating or preventing mucositis in a subject in need thereof who has been, is being, or is to be treated with an mTOR inhibitor, the method comprising administering a tacrolimus solution to the subject.

[0027] The present disclosure also provides for the use of a tacrolimus solution in a method of treating or preventing mucositis, wherein the treatment comprises administering the tacrolimus solution to a subject in need thereof who has been, is being, or is to be treated with an mTOR inhibitor.

[0028] The present disclosure also provides the use of a tacrolimus solution in the manufacture of a medicament for treating or preventing mucositis, wherein the treatment comprises administering the medicament to a subject in need thereof who has been, is being, or is to be treated with an mTOR inhibitor.

[0029] The present disclosure also provides a tacrolimus solution for use in a method of treating or preventing mucositis, the method comprising administering the tacrolimus solution to a subject in need thereof who has been, is being, or is to be treated with an mTOR inhibitor.

[0030] The present disclosure also provides an agent for treating or preventing mucositis, the agent comprising a tacrolimus solution, wherein the treatment comprises administering the agent to a subject in need thereof who has been, is being, or is to be treated with an mTOR inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 shows the dose-dependent antitumor effect of weekly repeated RMC-5552 treatment in the MCF7 xenograft model of human estrogen receptor-positive breast cancer in athymic nude mice. Abbreviations: ANOVA = analysis of variance; IP = intraperitoneal; QW = once a week. Figure 1A Shown are mean tumor responses from RMC-5552 administered at 1, 3, 10, or 30 mg / kg QW IP in transcutol / solutol formulation (n=12 / group).***P<0.0001, one-way ANOVA. Figure 1B Waterfall plots of responses at the end of individual studies are shown. Each animal is represented as an individual bar. Number of animals per group = 12. Numbers indicate the number of regressions (defined as >10% reduction in tumor volume compared to starting volume) at the corresponding dose in each group.

[0032] Figure 2 shows the anti-tumor activity of RMC-5552 in a TOV21G cell line-derived human ovarian cancer xenograft model following weekly administration. Abbreviations: ANOVA = analysis of variance; IP = intraperitoneal; QW = once a week. Figure 2AShown are mean tumor responses from RMC-5552 administered at 3 and 10 mg / kg QW IP in transcutol / solutol formulation (n=10, or n=5 in the 3 mg / kg dosing group).***P<0.0001, one-way ANOVA. Figure 2B Shown is a waterfall plot of individual tumor volumes at day 29 (endpoint for control animals). Each animal is represented as a separate bar. Number of animals per group = 10, or n = 5 in the 3 mg / kg dosing group. Numbers indicate the number of regressions (defined as a > 10% reduction in tumor volume compared to the starting volume) at the corresponding dose in each group. Figure 2C Shown is the duration of tumor response following 4 doses of 3 or 10 mg / kg QW IP RMC-5552. Figure 2D Reflects the regrowth of TOV21G tumors to 300 mm after treatment cessation 3 Kaplan-Meier survival analysis of the time to tumor volume. The median time to regrowth was 61 days for the RMC-5552 3 mg / kg group, while the survival of the 10 mg / kg dose group was indeterminate, extending to more than 73 days. The horizontal dashed line indicates the time to 50% tumor regrowth during treatment.

[0033] Figure 3 shows the anti-tumor activity of RMC-5552 in the HN009 patient-derived human HNSCC xenograft model following weekly administration. Abbreviations: ANOVA = analysis of variance; IP = intraperitoneal; QW = once weekly. Figure 3A Shown are mean volume graphs of RMC-5552 dosed at 3 or 10 mg / kg QW via intraperitoneal administration. **P<0.01, ***P<0.001, one-way ANOVA. Figure 3B Waterfall plots of individual tumor responses for all groups at day 51 post-implantation are shown. Each animal is represented as an individual bar. The number of tumor regressions (tumor regression defined as a >10% reduction in tumor volume compared to the starting volume) in each group is shown for the total mice in that group.

[0034] Figure 4 shows the pharmacokinetic-pharmacodynamic profiles of RMC-5552 in regulating tumor p4EBP1 and pS6RP in athymic nude mice bearing MCF7 tumors. Abbreviations: IP = intraperitoneal; p4EBP1 = phosphorylated eukaryotic translation initiation factor 4E binding protein 1; PK = pharmacokinetics; pS6RP = phosphorylated S6 ribosomal protein; u = unbound. Figure 4AShown is the dose-dependent modulation of tumor p4EBP1 following intraperitoneal administration of a single dose of RMC-5552 to nude mice bearing MCF7 tumors (left y-axis), plotted against PK unbound plasma concentration (nM), with a mouse plasma unbound fraction of 0.004 (right axis). Data represent mean ± SE (n=3). Figure 4B PK-pharmacodynamic relationships of modulation of tumor p4EBP1 and RMC-5552 plasma concentrations are shown for data derived from individual animals. The color of the symbols indicates the time of tissue harvest following intraperitoneal administration of a single dose of RMC-5552. Figure 4C Shown is the dose-dependent modulation of tumor pS6RP following intraperitoneal administration of a single dose of RMC-5552 to MCF7 tumor-bearing nude mice (left y-axis), plotted against PK unbound plasma concentration (nM) (right axis). Data represent mean ± SE (n=3).

[0035] Figure 5 Shown are human plasma concentration profiles of RMC-5552 on Cycle 1 Day 1 and Day 15. Abbreviations: C1D1 = Cycle 1 Day 1; C1D15 = Cycle 1 Day 15.

[0036] Figure 6 Shown is the expression of 4EBP3 mRNA in human blood samples.

[0037] Figure 7 The best percent change from baseline in target lesions for efficacy evaluable patients treated with ≥6 mg RMC-5552 is shown. Abbreviations: HCC = hepatocellular carcinoma; PD = progressive disease; PR = partial response; SD = stable disease; QW = once a week. * Patient received one 12 mg dose followed by 6 mg doses per week. Patient was classified as PR due to persistent non-target lesions. Patient has received RMC-5552 for 6 months. # Patient received one 10 mg dose followed by 6 mg doses per week.

[0038] Figure 8 Shown are changes in ctDNA burden for dose cohorts treated with RMC-5552 at doses ranging from 1.6 mg to 10 mg.

[0039] Fig. 9 Molecular and radiographic responses to RMC-5552 are shown for subjects treated with 6 mg and above of RMC-5552 as assessed by RECIST (Response Evaluation Criteria in Solid Tumors). X = Subject with pathogenic PTEN, PIK3CA or TSC1 / 2 variants at baseline.

[0040] Fig.10Overall molecular response, changes in ctDNA burden for pathogenic / likely pathogenic PTEN variants, pathogenic / likely pathogenic TSC1 / 2 variants, and pathogenic / likely pathogenic PIK3CA variants are depicted graphically. DETAILED DESCRIPTION

[0041] The present disclosure relates to methods of treating a disease or disorder (e.g., cancer) with a compound (e.g., RMC-5552). In some embodiments, the present disclosure provides methods for delaying, preventing, or treating a disease or disorder (e.g., cancer) by administering a compound (e.g., RMC-5552). G12C inhibitors) by developing acquired resistance.

[0042] The method comprises administering the compound (e.g., RMC-5552) at a specific dose. For example, in some embodiments, the compound (e.g., RMC-5552) is administered at a dose of about 3 mg / week to about 25 mg / week.

[0043] It is unexpectedly found that the dosage of the compound as described herein (i.e., RMC-5552) is effective when treating a disease or disorder of a subject, while keeping the subject tolerable. The common point of drug therapy failure is that the subject cannot tolerate the side effects of the drug, while continuing to use the drug in an amount that effectively treats the disease. Low doses of the drug can reduce or eliminate side effects, but can lead to ineffective disease treatment. For example, the side effects associated with multiple cancer treatments include stomatitis / mucositis, decreased appetite and fatigue, anemia, dehydration, hyponatremia, nausea and vomiting. It is unexpectedly found that the dosage of the compound of the present disclosure (i.e., RMC-5552) does not produce such side effects under the severity that the drug use needs to be reduced to below the therapeutically effective amount.

[0044] Unless otherwise indicated, as used above and throughout this disclosure, the following terms should be understood to have the following meanings. If a term is missing, the conventional term as known to those skilled in the art prevails.

[0045] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0046] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element.

[0047] As used herein, the term "and / or" means "and" or "or" or both.

[0048] In order to provide a more concise description, some quantitative expressions given herein are not limited by the term "about". It should be understood that, whether or not the term "about" is explicitly used, each amount given herein means the actual given value, and also means the approximate value of this given value reasonably inferred based on the ordinary technology of the art, including equivalent values ​​and approximate values ​​due to the experimental and / or measurement conditions of this given value. As long as the yield is given as a percentage, such a yield refers to the mass of the entity giving the yield relative to the maximum amount of the same entity obtainable under specific stoichiometric conditions. Unless otherwise indicated differently, the concentration given as a percentage refers to the mass ratio.

[0049] As used in this disclosure, unless otherwise indicated, the term "disorder" means, and is used interchangeably with, a disease, condition, or illness.

[0050] The term "inhibitor" means a compound that prevents a biomolecule (e.g., protein, nucleic acid) from completing or initiating a reaction. The inhibitor can inhibit the reaction in a competitive, non-competitive or non-competitive manner. Exemplary inhibitors include, but are not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimics, peptides, peptide mimics, antibodies, small molecules, chemicals, analogs of binding sites of mimic enzymes, receptors or other proteins (e.g., proteins involved in signal transduction), therapeutic agents, pharmaceutical compositions, drugs, and combinations of these. In some embodiments, the inhibitor can be a nucleic acid molecule, including but not limited to siRNA that reduces the amount of functional proteins in cells. Therefore, compounds that are said to be "capable of inhibiting" a specific protein (e.g., mTOR or RAS) include any such inhibitor.

[0051] As used herein, the term "therapeutic agent" refers to any substance, such as a compound or composition, that is capable of treating a disease or disorder. In some embodiments, therapeutic agents that can be used in conjunction with the present disclosure include, but are not limited to, mTOR inhibitors, RAS inhibitors (such as, for example, KRAS inhibitors (e.g., KRAS G12C inhibitors)) and certain cancer chemotherapeutic agents.

[0052] As used herein, the term "treatment" or "treating" with respect to a subject refers to improving at least one symptom, condition or marker of a disease or disorder in a subject, either directly or by enhancing the effect of another treatment. Treatment includes curing, improving or at least partially ameliorating a disorder, and may include even minimal changes or improvements in one or more measurable markers of the disease or disorder being treated. "Treatment" or "treating" does not necessarily indicate complete eradication or cure of a disease or disorder or its associated symptoms. A subject receiving such treatment is any subject in need. Exemplary markers of clinical improvement will be clear to those skilled in the art. mTOR inhibitors

[0053] As used herein, the term "mTOR inhibitor" refers to a compound that inhibits mTOR activity (e.g., kinase activity). Examples of mTOR inhibitors include, but are not limited to, RMC-5552, everolimus, sirolimus, albumin-bound sirolimus (nab-sirolimus), ΓNK128, PP242, PP121, MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226, SF1126, Torin 1, Torin 2, WYE 687, WYE 687 salt (e.g., hydrochloride), PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, and PKI-587. In some embodiments, the mTOR inhibitor is an inhibitor that is more selective for mTORC1 relative to mTORC2. In some embodiments, the mTOR inhibitor is an inhibitor that is more selective for mTORC2 relative to mTORC1. In embodiments, the mTOR inhibitor is an active site mTOR inhibitor. As used herein, an "active site mTOR inhibitor" refers to a compound that inhibits the activity of mTOR (e.g., kinase activity) and binds to the active site of mTOR (e.g., ATP binding site, overlaps with the ATP binding site, accesses the ATP binding site of mTOR through ATP blocking).

[0054] In some embodiments, the compounds employed in the embodiments of the present disclosure (e.g., RMC-5552) may sometimes be referred to herein as "bi-steric mTOR inhibitors" or "bi-steric inhibitors of mTOR". The terms "bi-steric mTOR inhibitor" and "bi-steric inhibitor of mTOR" are used interchangeably in the present disclosure to refer to two pharmacophores in a single compound. One pharmacophore binds to the well-known FRB (FKBP12-rapamycin binding) site on mTORC1, and the other binds to the mTOR kinase active site. As a result of these two binding interactions, such compounds exhibit two biologically useful characteristics: (1) selectivity for mTORC1 over mTORC2, which is a characteristic of the natural compound rapamycin, and (2) deep inhibition of mTORC1, which is a characteristic of known active site inhibitors. These properties enable selective inhibition of phosphorylation of mTORC1 substrates (including 4EBP1). Non-limiting examples of dual-site mTOR inhibitors can be found in WO 2019212991, WO 2019212990, and WO 2018204416, which are incorporated herein by reference in their entirety. In some embodiments, the dual-site mTOR inhibitor has a molecular weight between 1600 and 2100 Da (including the end value) and exhibits selective (>10-fold) inhibition of mTORC1 over mTORC2. In some embodiments, the two pharmacophores are joined by a linker. The linker can be any suitable linker, such as a PEG linker, or a linker described in: Hoang Thi, Thai Thanh et al. "The Importance of Poly(ethylene glycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation." Polymers Vol. 12, 2 298. February 2, 2020.

[0055] In some embodiments, the mTOR inhibitor is a compound of Formula Ic: or its stereoisomers, tautomers or oxirane isomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R 32 It is -H, =O, -OR 3 , -N3 or -OC(=Z 1 )-R 32a ; R 28 is -H, (C1-C6) alkyl or -C(=Z1 )-R 28a ; R 40 is -H or -C (=Z 1 )-R 40a ; When R 28 and R 40 When it is H, then R 32 Not = O; Each Z 1 independently O or S; R 28a , R 32a and R 40a Independently - A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; -L 2 -A 1 -L 1 -A 2 -L 3 -B; -O-(C1-C6)alkyl; or -O-(C6-C 10 )aryl; wherein -O-(C6-C 10 ) the aryl group of the aryl group is unsubstituted or substituted with 1 to 5 substituents selected from -NO2 and halogen; A 1 and A 2 Independently non-existent or independently selected from As shown in A 1 The key on the left is -C(=Z 1 )- or L 2 Combined; and wherein as drawn in A 2 The key on the right side of the part is connected to B or L 3 Combine; Each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; Each X is independently absent or is 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; Each X 1 is independently a heteroarylene or heterocyclylene ring; Each W is independently absent or is 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; Each W 1 is independently a heteroarylene or heterocyclylene ring; Each G is independently absent or is a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; G 1 and G 2 are each independently a heteroarylene or heterocyclylene ring; each L 1 Independently selected from L 2 and L 3 Independently non-existent or independently selected from Each B is independently selected from Each TB 1 Independently selected from NR 3 -(C(R 3 )2) n -、 NR 3 -(C(R 3 )2) n -(C6-C 10 )arylene-(C(R 3 )2) n -、 NR 3 -(C(R 3 )2) n -heteroarylene-, NR 3 -(C(R 3 )2) n -heteroarylene-(C(R 3 )2) n -、 (C6-C 10 ) arylene-, NR 3 -(C(R 3 )2) n -NR 3 C(O)-, NR 3 -(C(R 3 )2) n -heteroarylene-heterocyclylene-(C6-C 10 ) arylene-, Heteroarylene-heterocyclylene-(C6-C 10 ) arylene-, NR 3 -(C(R 3 )2) n -S(O)2-arylene-C(O)- and NR 3 -(C(R 3 )2) n -S(O)2-arylene-(C(R 3 )2) n -, where as drawn in B 1 Left Key and A 2 , L 3 or L 1 and wherein heteroarylene, heterocyclylene and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen or hydroxy; Each R 3 are independently H or (C1-C6)alkyl; Each R 4 are independently H, (C1-C6) alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C6-C 10 ) aryl, wherein the heteroaryl, heterocyclyl, and aryl are optionally substituted by -N(R 3 )2.-OR 3 , halogen, (C1-C6) alkyl, -(C1-C6) alkylene-heteroaryl, -(C1-C6) alkylene-CN, -C(O)NR 3 -heteroaryl, or -C(O)NR 3 - Heterocyclyl substitution; Each R 5 are independently H, (C1-C6)alkyl, -C(O)OR 3 , or -N(R 3 )2, wherein the alkyl group of the (C1-C6)alkyl group is optionally replaced by -N(R 3 )2OR 3 replace; Each R 6 are independently H, (C1-C6)alkyl, -C(O)OR 3 , or -N(R 3 )2, wherein the alkyl group of the (C1-C6)alkyl group is optionally replaced by -N(R 3 )2OR 3 replace; Each R 7 are independently H, (C1-C6)alkyl, -C(O)OR 3 , or -N(R 3)2, wherein the alkyl group of the (C1-C6)alkyl group is optionally replaced by -N(R 3 )2OR 3 replace; Each R 8 are independently H, (C1-C6)alkyl, -C(O)OR 3 , or -N(R 3 )2, wherein the alkyl group of the (C1-C6)alkyl group is optionally replaced by -N(R 3 )2OR 3 replace; Each Y is independently C(R 3 )2 or key; Each n is independently an integer from 1 to 12; Each o is independently an integer from 0 to 30; Each p is independently an integer from 0 to 12; Each Q is independently an integer from 0 to 30; and Each r is independently an integer from 1 to 6. See, e.g., WO 2019212990, which is incorporated herein by reference in its entirety.

[0056] In some embodiments, the two pharmacophores described in Formula Ic are joined by a linker, such as one of the linkers described in: Hoang Thi, Thai Thanh et al. "The Importance of Poly(ethyleneglycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation." Polymers Vol. 12, 2 298. Feb. 2, 2020.

[0057] In another embodiment of the present disclosure, the mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) is an enantiomer. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In other embodiments, the compound is a (+) or (-) enantiomer.

[0058] It should be understood that all isomeric forms are included in the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0059] mTOR inhibitors (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. The method of the present disclosure is intended to consider all stereoisomeric forms of mTOR inhibitors (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) and mixtures thereof, including racemic mixtures. In addition, the present disclosure includes methods comprising all geometric and positional isomers. For example, if the mTOR inhibitor (e.g., dual-site mTOR inhibitor, e.g., RMC-5552) contains both double bonds or fused rings, both cis and trans forms, and mixtures, it is included within the scope of the present disclosure. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compound may be in racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may be reflected as data collected in racemic form, enantiomerically pure form, or any other form in terms of stereochemistry.

[0060] As used herein, the term "tautomer" can refer to a group of compounds that have the same number of atoms and atom types, but different bond connectivity and are mutually balanced. A "tautomer" is a single member of this group of compounds. Typically, a single tautomer is drawn, but it is understood that this single structure can represent all possible tautomers that may exist. Examples can include enol-keto tautomerism. When drawing ketones, it is understood that both the enol and keto forms are part of the present disclosure. The mTOR inhibitors of the present disclosure (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) can exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are considered herein as part of the method of the present disclosure.

[0061] In addition to the tautomers that may exist at all amide, carbonyl and oxime groups in the mTOR inhibitors of the present disclosure, the compounds in this family are also easily interconverted between two major isomeric forms, referred to as pyran and oxirane isomers (shown below), by ring opening species. This interconversion can be promoted by magnesium ions, weakly acidic conditions or alkylamine salts, as described in the following references: i) Hughes, PF; Musser, J.; Conklin, M.; Russo, R. 1992. Tetrahedron Lett. 33(33):4739-32., ii) Zhu, T. 2007. US Patent 7,241,771; Wyeth., iii) Hughes, PF 1994. US Patent 5,344,833; American Home Products Corp. The following schemes show interconversions between pyran and oxirane isomers in compounds, including compounds according to Formula Ic.

[0062] Since this interconversion occurs under mild conditions and the thermodynamic equilibrium position between different members of the compound of Formula Ic may change, two isomers are considered for the compound of Formula Ic. For the sake of brevity, the pyran isomeric forms of all intermediates and compounds of Formula Ic are shown, however, it should be understood that mTOR inhibitors (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) can exist in their oxirane forms. All such oxirane forms are considered herein as part of the methods of the present disclosure.

[0063] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of this disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Solvates in which water is a solvent molecule are generally referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing variable amounts of water.

[0064] As used herein, the term "one or more salts" refers to acidic salts formed with inorganic acids and / or organic acids, and basic salts formed with inorganic bases and / or organic bases. In addition, when the compound contains a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, carboxylic acid), zwitterions ("inner salts") may be formed and included in the term "one or more salts" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of mTOR inhibitors (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) may be formed, for example, by reacting the compound with an amount (such as an equivalent amount) of an acid or base in a medium (such as a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization. The compounds of the present disclosure may include pharmaceutically acceptable salts of the compounds disclosed herein. Representative "pharmaceutically acceptable salts" can include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, edetate, camphorsulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, methanesulfonate, methyl Bromide, methylnitrate, methylsulfate, mucilagen, naphthylsulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, 1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, and valerate.

[0065] "Pharmaceutically acceptable salts" may also include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" may refer to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and can be formed with the following acids: inorganic acids, such as but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; and organic acids, such as but not limited to acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, rich Maleic acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0066] "Pharmaceutically acceptable base addition salts" may refer to those salts that retain the biological effectiveness and properties of the free acid, without being biologically or otherwise undesirable. These salts may be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. For example, inorganic salts may include, but are not limited to, ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases can include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

[0067] Unless otherwise stated, structures depicted herein may also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of a hydrogen atom with deuterium or tritium, or with 13 C or 14C replaces the carbon atom, or uses 15 N replaces nitrogen atoms, or 17 O or 18 Compounds having the present structures except for the substitution of an oxygen atom with O are within the scope of the present disclosure. Such isotopically labeled compounds are useful as research or diagnostic tools.

[0068] The term RMC-6272 refers to a dual-site mTOR inhibitor with the following structure: RMC-6272 exhibits potent and selective (>10-fold) inhibition of mTORC1 versus mTORC2. Also contemplated herein are stereoisomers, tautomers, and oxirane isomers of RMC-6272, or a pharmaceutically acceptable salt of any of the foregoing.

[0069] The term RMC-5552 refers to a dual-site mTOR inhibitor with the following structure:

[0070] In some embodiments, the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0071] In some embodiments, the dual-site mTOR inhibitor is Or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Mechanistic target of rapamycin (mTOR)

[0072] The term "mTOR" refers to the protein "mechanistic target of rapamycin (serine / threonine kinase)" or "mammalian target of rapamycin". The term "mTOR" may refer to the nucleotide sequence or protein sequence of human mTOR (e.g., Entrez 2475, Uniprot P42345, RefSeq NM_004958, or RefSeq NP_004949) (SEQ ID NO: 1). The term "mTOR" may include both the nucleotide sequence or protein of the wild-type form and any mutant thereof. In some embodiments, "mTOR" is wild-type mTOR. In some embodiments, "mTOR" is one or more mutant forms. The term "mTOR" XYZ may refer to the nucleotide sequence or protein of a mutant mTOR, wherein the Y-numbered amino acid of mTOR typically has an X amino acid in the wild type and a Z amino acid in the mutant. In some embodiments, mTOR is human mTOR. In some embodiments, mTOR has a nucleotide sequence corresponding to reference number GL206725550 (SEQ ID NO: 2). In some embodiments, mTOR has a nucleotide sequence corresponding to RefSeq NM_004958.3 (SEQ ID NO: 2). In some embodiments, mTOR has a protein sequence corresponding to reference number GL4826730 (SEQ ID NO: 1). In some embodiments, mTOR has a protein sequence corresponding to RefSeq NP_004949.1 (SEQ ID NO: 1). In some embodiments, mTOR has the following amino acid sequence:

[0073] In some embodiments, the mTOR is a mutant mTOR. In some embodiments, the mutant mTOR is associated with a disease that is not associated with wild-type mTOR. In some embodiments, the mTOR may comprise at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to the above sequences.

[0074] The term "mTORC1" refers to a protein complex including mTOR and Raptor (mTOR regulatory-related protein). mTORC1 may also include MLST8 (mammalian lethal protein SEC 13 protein 8), PRAS40 and / or DEPTOR. mTORC1 can be used as a nutrient / energy / redox sensor and regulator for protein synthesis. The term "mTORC1 pathway" or "mTORC1 signal transduction pathway" may refer to a cellular pathway including mTORC1. The mTORC1 pathway includes pathway components upstream and downstream of mTORC1. The mTORC1 pathway is a signal transduction pathway regulated by regulating mTORC1 activity. In some embodiments, the mTORC1 pathway is a signal transduction pathway regulated by regulating mTORC1 activity rather than by regulating mTORC2 activity. In some embodiments, the mTORC1 pathway is a signal transduction pathway regulated to a greater extent by regulating mTORC1 activity than by regulating mTORC2 activity.

[0075] The term "mTORC2" refers to a protein complex including mTOR and RICTOR (rapamycin-insensitive partner of mTOR). mTORC2 may also include GβL, mSIN1 (mammalian stress-activated protein kinase interacting protein 1), Protor1 / 2, DEPTOR, TTI1 and / or TEL2. mTORC2 can regulate cell metabolism and cytoskeleton. The term "mTORC2 pathway" or "mTORC2 signal transduction pathway" may refer to a cell pathway comprising mTORC2. The mTORC2 pathway includes pathway components upstream and downstream of mTORC2. The mTORC2 pathway is a signal transduction pathway regulated by regulating mTORC2 activity. In some embodiments, the mTORC2 pathway is a signal transduction pathway regulated by regulating mTORC2 activity rather than by regulating mTORC1 activity. In some embodiments, the mTORC2 pathway is a signal transduction pathway regulated to a greater extent by regulating mTORC2 activity than by regulating mTORC1 activity.

[0076] The term "rapamycin" or "sirolimus" refers to a macrolide produced by the bacterium Streptomyces hygroscopicus. Rapamycin can prevent the activation of T cells and B cells. Rapamycin has the IUPAC name (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexahydro-9,27-dihydroxy-3-[ (lR)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1c][1,4]-oxazacyclotriacontane-1,5,11,28,29(4H,6H,31H)-pentanone. Rapamycin has CAS number 53123-88-9. Rapamycin can be produced synthetically (e.g., by chemical synthesis) or by using a production method that does not include Streptomyces hygroscopicus.

[0077] "Analog" is used according to its plain ordinary meaning in chemistry and biology, and refers to a compound that is structurally similar to another compound, the so-called "reference" compound, but differs in composition (e.g., the replacement of an atom by an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group by another, or the absolute stereochemistry of one or more chiral centers of the reference compound (including isomers thereof)).

[0078] The term "rapamycin analog" or "rapalog" refers to an analog or derivative (eg, a prodrug) of rapamycin.

[0079] The term "FKBP" refers to the protein peptidyl-prolyl cis-trans isomerase. For non-limiting examples of FKBP, see Cell Mol Life Sci. 2013 September; 70(18): 3243-75. In some embodiments, "FKBP" may refer to "FKBP-12" or "FKBP 12" or "FKBP 1A". In some embodiments, "FKBP" may refer to a human protein. The term "FKBP" includes wild-type and mutant forms of the protein. In some embodiments, "FKBP" may refer to a wild-type human protein. In some embodiments, "FKBP" may refer to a wild-type human nucleic acid. In some embodiments, FKBP is a mutant FKBP. In some embodiments, a mutant FKBP is associated with a disease that is not associated with a wild-type FKBP. In some embodiments, the FKBP comprises at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to the above wild-type FKBP.

[0080] The term "FKBP-12" or "FKBP 12" or "FKBP1A" may refer to the protein "peptidyl-prolyl cis-trans isomerase FKBP 1A". In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP 1A" may refer to a human protein. The term "FKBP-12" or "FKBP 12" or "FKBP 1A" includes wild-type and mutant forms of the protein. In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP 1A" may refer to a protein related to Entrez gene 2280, OMIM 186945, UniProt P62942, and / or RefSeq (protein) NP_000792 (SEQ ID NO: 3). In some embodiments, the reference numbers immediately above may refer to proteins and related nucleic acids known as of the filing date of the present application. In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP 1A" may refer to a wild-type human protein. In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP1A" may refer to a wild-type human nucleic acid. In some embodiments, FKBP-12 is a mutant FKBP-12. In some embodiments, the mutant FKBP-12 is associated with a disease that is not associated with wild-type FKBP-12. In some embodiments, the FKBP-12 may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to wild-type FKBP-12. In some embodiments, FKBP-12 has a protein sequence corresponding to reference number GI: 206725550. In some embodiments, FKBP-12 has a protein sequence corresponding to RefSeq NP_000792.1 (SEQ ID NO: 3).

[0081] The term "4E-BP1" or "4EBP1" or "EIF4EBP1" refers to the protein "Eukaryotic translation initiation factor 4E binding protein 1". In some embodiments, "4E-BP1" or "4EBP1" or "EIF4EBP 1" may refer to a human protein. The term "4E-BP 1" or "4EBP 1" or "EIF4EBP1" includes wild-type and mutant forms of the protein. In some embodiments, "4E-BP1" or "4EBP1" or "EIF4EBP1" may refer to a protein related to Entrez gene 1978, OMIM 602223, UniProt Q13541, and / or RefSeq (protein) NP_004086 (SEQ ID NO: 4). In some embodiments, the reference numbers immediately above may refer to proteins and related nucleic acids known as of the filing date of the present application. In some embodiments, "4E-BP 1" or "4EBP1" or "EIF4EBP1" may refer to a wild-type human protein. In some embodiments, "4E-BP1" or "4EBP1" or "EIF4EBP1" may refer to a wild-type human nucleic acid. In some embodiments, 4EBP1 is a mutant 4EBP1. In some embodiments, mutant 4EBP1 is associated with a disease that is not associated with wild-type 4EBP1. In some embodiments, the 4EBP1 may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to wild-type 4EBP1. In some embodiments, the 4EBP1 has a protein sequence corresponding to reference number GL4758258. In some embodiments, the 4EBP1 has a protein sequence corresponding to RefSeqNP_004086.1 (SEQ ID NO: 4).

[0082] The term "Akt" refers to a serine / threonine-specific protein kinase involved in cellular processes (such as glucose metabolism, apoptosis, proliferation, and other functions), also known as "protein kinase B" (PKB) or "Akt1". In some embodiments, "Akt" or "AM" or "PKB" may refer to a human protein. The term "Akt" or "Akt1" or "PKB" includes wild-type and mutant forms of the protein. In some embodiments, "Akt" or "Akt1" or "PKB" may refer to a protein associated with Entrez gene 207, OMIM 164730, UniProt P31749, and / or RefSeq (protein) NP_005154 (SEQ ID NO: 5). In some embodiments, the reference numbers immediately above may refer to proteins and related nucleic acids known from the filing date of the present application. In some embodiments, "Akt" or "Akt1" or "PKB" may refer to a wild-type human protein. In some embodiments, "Akt" or "Akt1" or "PKB" may refer to a wild-type human nucleic acid. In some embodiments, Akt is a mutant Akt. In some embodiments, the mutant Akt is associated with a disease that is not associated with wild-type Akt. In some embodiments, the Akt may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any range derivable therein) compared to wild-type Akt. In some embodiments, the Akt has a protein sequence corresponding to reference number GI: 62241011. In some embodiments, the Akt has a protein sequence corresponding to RefSeq NP_005154.2 (SEQ ID NO: 5).

[0083] As used herein, the term "mutation" indicates any modification to a nucleic acid and / or polypeptide that produces an altered nucleic acid or polypeptide. The term "mutation" may include, for example, point mutations, deletions or insertions of single or multiple residues in a polynucleotide, changes occurring within a protein coding region of a gene, and changes in regions outside of a protein coding sequence (such as, but not limited to, regulatory or promoter sequences), and amplification and / or chromosome breakage or translocation.

[0084] When referring to a cell “subtype” (e.g., KRAS G12C Subtype, KRAS G12S Subtype, KRAS G12D Subtype, KRAS G12VWhen a cell is classified as a "KRAS subtype," it means that the cell contains a genetic mutation that encodes a change in a protein of the indicated type. G12C Cells of the "subtype" contain at least one KRAS allele that encodes an amino acid substitution at position 12 that replaces cysteine ​​with glycine ( G12C ); and, similarly, specific subtypes (e.g., KRAS G12D 、KRAS G12S and KRAS G12V subtype) contain cells with the indicated mutations (e.g., KRAS G12D Mutation, KRAS G12S Mutation or KRAS G12V Unless otherwise indicated, all amino acid position substitutions referred to herein (e.g., KRAS G12C "G12C" in the referenced protein) corresponds to the substitution in the human form of the referenced protein, i.e., KRAS G12C Refers to a G→C substitution in position 12 of human KRAS. Treatment

[0085] The present disclosure provides a method of treating a disease or disorder mediated by mTOR by administering a dose of an mTOR inhibitor (eg, a dual-site mTOR inhibitor such as RMC-5552) to a subject suffering from or susceptible to a disease or disorder mediated by mTOR.

[0086] In some embodiments, the method comprises administering an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) as a monotherapy. The term "monotherapy" refers to a treatment method that comprises administering a single therapeutic agent to a subject, optionally as a pharmaceutical composition.

[0087] Some embodiments relate to methods of treating a subject having cancer by administering to the subject a dual-site mTOR inhibitor at a dose of about 3 mg / week to about 25 mg / week; Among them, dual-site mTOR inhibitors are or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0088] In some embodiments, the cancer is salivary gland cancer, and the method comprises administering to the subject a dual-site mTOR inhibitor at a dose of about 3 mg / week to about 25 mg / week; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0089] In some embodiments, the dosage is about 4 mg / week to about 25 mg / week, about 4 mg / week to about 20 mg / week, about 4 mg / week to about 16 mg / week, about 4 mg / week to about 14 mg / week, about 4 mg / week to about 12 mg / week, about 4 mg / week to about 10 mg / week, about 4 mg / week to about 9 mg / week, about 4 mg / week to about 8 mg / week, about 4 mg / week to about 7 mg / week, about 4 mg / week to about 6 mg / week, about 5 mg / week to about 25 mg / week, about 5 mg / week to about 20 mg / week, about 5 mg / week to about 16 mg / week, about 5 mg / week to about 14 mg / week, about 5 mg / week to about 12 mg / week. about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 9 mg / week, about 5 mg / week to about 8 mg / week, about 5 mg / week to about 7 mg / week, about 5 mg / week to about 6 mg / week, about 6 mg / week to about 25 mg / week, about 6 mg / week to about 20 mg / week, about 6 mg / week to about 16 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week, about 6 mg / week to about 7 mg / week, about 7 mg / week to about 25 mg / week. g / week, about 7 mg / week to about 20 mg / week, about 7 mg / week to about 16 mg / week, about 7 mg / week to about 14 mg / week, about 7 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 7 mg / week to about 9 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 25 mg / week, about 8 mg / week to about 20 mg / week, about 8 mg / week to about 16 mg / week, about 8 mg / week to about 14 mg / week, about 8 mg / week to about 12 mg / week, about 8 mg / week to about 10 mg / week, about 9 mg / week to about 25 mg / week, about 9 mg / week to about 20 mg / week g / week, about 9 mg / week to about 16 mg / week, about 9 mg / week to about 14 mg / week, about 9 mg / week to about 12 mg / week, about 9 mg / week to about 10 mg / week, about 10 mg / week to about 25 mg / week, about 10 mg / week to about 20 mg / week, about 10 mg / week to about 16 mg / week, about 10 mg / week to about 14 mg / week, about 10 mg / week to about 12 mg / week, about 11 mg / week to about 25 mg / week, about 11 mg / week to about 20 mg / week, about 11 mg / week to about 16 mg / week, about 11 mg / week to about 14 mg / week, or about 11 mg / week to about 12 mg / week.

[0090] In some embodiments, the dosage is about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week, or about 25 mg / week.

[0091] It is unexpectedly observed that the dual-site mTOR inhibitor (i.e., RMC-5552) of dosage of 1.6mg / week to 6mg / week shows a dose-proportional exposure increase, and the dosage higher than 6mg / week shows an increase exceeding dose-proportional. The dose-proportional increase is generally preferred in the dosage regimen because it provides better control of target exposure and is generally related to the desired drug clearance rate. These problems are generally balanced with the need for high doses to provide the efficacy of disease treatment. Therefore, in some embodiments, dosage is in or close to 6mg / week (for example, about 5mg / week to about 9mg / week, about 6mg / week to about 9mg / week, about 6mg / week to about 8mg / week, about 5mg / week, about 5.5mg / week, about 6mg / week, about 6.5mg / week, about 7mg / week, about 7.5mg / week, about 8mg / week, about 8.5mg / week or about 9mg / week) dose-proportional inflection point.

[0092] It was also unexpectedly observed that there was a steep dose-response relationship for doses above about 6 mg / week (e.g., between 6 mg / week and 12 mg / week). Thus, in some embodiments, doses above about 6 mg / week are used. Doses within these ranges may be intolerable due to side effects (e.g., mucositis). As described herein, tacrolimus (e.g., tacrolimus mouthwash; see extended discussion of tacrolimus below) unexpectedly can reduce side effects and thereby enable higher doses. Thus, in some embodiments, doses above about 6 mg / week are used in combination with tacrolimus.

[0093] In some embodiments, a high dose (e.g., higher than about 6 mg / week) is used first and then the dose is reduced. For example, in some embodiments, a dose higher than about 6 mg / week (i.e., higher than the dose proportional increase threshold) is applied for one or several weeks, and a dose lower than about 6 mg / week (i.e., close to or lower than the dose proportional increase threshold) is subsequently applied. In some embodiments, there is a drug holiday (e.g., 1, 2, 3, 4, or 5 weeks) between the high dose and the low dose. In some embodiments, the dose for the first 1, 2, 3, 4, or 5 weeks is higher than the dose for the following weeks. In some embodiments, the dose for the first week is higher than the dose for the following weeks.

[0094] In some embodiments, the dosage for the first 1, 2, 3, 4, or 5 weeks is from about 6 mg / week to about 25 mg / week, from about 6 mg / week to about 20 mg / week, from about 6 mg / week to about 16 mg / week, from about 6 mg / week to about 14 mg / week, from about 6 mg / week to about 12 mg / week, from about 6 mg / week to about 10 mg / week, from about 8 mg / week to about 25 mg / week, from about 8 mg / week to about 20 mg / week, from about 8 mg / week to about 16 mg / week, from about 8 mg / week to about 14 mg / week, from about 8 mg / week to about 12 mg / week, from about 8 mg / week to about 10 mg / week, from about 10 mg / week to about 25 mg / week, from about 10 mg / week to about 20 mg / week, from about 10 mg / week to about 16 mg / week, from about 10 mg / week to about 14 mg / week, or from about 10 mg / week to about 12 mg / week. In some embodiments, the dosage for the first 1, 2, 3, 4 or 5 weeks is about 10 mg / week to about 12 mg / week. In some embodiments, the dosage for the first week is about 10 mg / week to about 12 mg / week.

[0095] In some embodiments, the dosage for the first 1, 2, 3, 4 or 5 weeks is about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week. In some embodiments, the dosage for the first 1, 2, 3, 4 or 5 weeks is about 10 mg / week. In some embodiments, the dosage for the first 1, 2, 3, 4 or 5 weeks is about 11 mg / week. In some embodiments, the dosage for the first 1, 2, 3, 4, or 5 weeks is about 12 mg / week. In some embodiments, the dosage for the first week is about 10 mg / week. In some embodiments, the dosage for the first week is about 11 mg / week. In some embodiments, the weekly dosage is about 12 mg / week.

[0096] In some embodiments, 1, 2, 3, 4 or 5 weeks after the first 1, 2, 3, 4 or 5 weeks of doses are not administered. In some embodiments, 1, 2, 3, 4 or 5 weeks after the first week of doses are not administered.

[0097] In some embodiments, the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks is about 3 mg / week to about 12 mg / week, about 3 mg / week to about 10 mg / week, about 3 mg / week to about 8 mg / week, about 3 mg / week to about 6 mg / week, about 4 mg / week to about 12 mg / week, about 4 mg / week to about 10 mg / week, about 4 mg / week to about 8 mg / week, about 4 mg / week to about 6 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week. / week to about 10 mg / week, about 5 mg / week to about 8 mg / week, about 5 mg / week to about 6 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 6 mg / week to about 8 mg / week, about 6 mg / week to about 7 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 10 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week. In some embodiments, the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks is about 3 mg / week to about 12 mg / week.

[0098] In some embodiments, the dose after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks is about 3 mg / week, about 3.5 mg / week, about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week or about 10 mg / week. In some embodiments, the dose after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks is about 6 mg / week.

[0099] For example, in some embodiments, the dosage for the first 1, 2, 3, 4, or 5 weeks is about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week, or about 25 mg / week; No administration for 0, 1, 2, 3, 4, or 5 weeks thereafter; Subsequent doses are about 3 mg / week to about 12 mg / week, about 3 mg / week to about 10 mg / week, about 3 mg / week to about 8 mg / week, about 3 mg / week to about 6 mg / week, about 4 mg / week to about 12 mg / week, about 4 mg / week to about 10 mg / week, about 4 mg / week to about 8 mg / week, about 4 mg / week to about 6 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week. / week to about 8 mg / week, about 5 mg / week to about 6 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 6 mg / week to about 8 mg / week, about 6 mg / week to about 7 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 10 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week.

[0100] Also for example, in some embodiments, the dosage for the first 1, 2, 3, 4, or 5 weeks is from about 6 mg / week to about 25 mg / week, from about 6 mg / week to about 20 mg / week, from about 6 mg / week to about 16 mg / week, from about 6 mg / week to about 14 mg / week, from about 6 mg / week to about 12 mg / week, from about 6 mg / week to about 10 mg / week, from about 8 mg / week to about 25 mg / week, from about 8 mg / week to about 20 mg / week, from about 8 mg / week to about 16 mg / week, from about 8 mg / week to about 14 mg / week, from about 8 mg / week to about 12 mg / week, from about 8 mg / week to about 10 mg / week, from about 10 mg / week to about 25 mg / week, from about 10 mg / week to about 20 mg / week, from about 10 mg / week to about 16 mg / week, from about 10 mg / week to about 14 mg / week, or from about 10 mg / week to about 12 mg / week; No administration for 0, 1, 2, 3, 4, or 5 weeks thereafter; Subsequent doses are about 3 mg / week, about 3.5 mg / week, about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, or about 10 mg / week.

[0101] In some embodiments, after a few (e.g., 1, 2, 3, 4, or 5) weeks of administration at a lower dose, there may be another drug holiday (e.g., 0, 1, 2, 3, 4, or 5 weeks of no administration) and / or another reduction in dosage. In some embodiments, this is followed by more drug holidays and / or dose reductions. In some embodiments, the dosage is gradually reduced during treatment. In some embodiments, the dosage is reduced by about 1 mg / week, about 2 mg / week, about 3 mg / week, about 4 mg / week, about 5 mg / week, or about 6 mg / week every 1, 2, 3, 4, or 5 weeks. In some embodiments, there is an administration drug holiday between each dose reduction.

[0102] The administration of the disclosed compounds or compositions can be accomplished via any administration route of the therapeutic agent. These routes can include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, topical, intrathecal, or intracranial administration.

[0103] In some embodiments, administration can include oral administration to the subject, administration as a suppository, external contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration or implantation of a slow release device (e.g., a micro-osmotic pump). Administration can be carried out by any route, including parenteral and transmucosal (e.g., buccal, sublingual, through the jaw, through the gums, through the nose, through the vagina, through the rectum, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other delivery methods include, but are not limited to, the use of liposome formulations, intravenous infusions, transdermal patches, etc. The compositions of the present disclosure can be delivered transdermally by external routes and by preparations as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, paints, powders and aerosols. Oral formulations include tablets, pills, powders, lozenges, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like suitable for ingestion by a patient. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present disclosure may additionally include components that provide sustained release and / or comfort. Such components include high molecular weight anionic mucosimulating polymers, gelling polysaccharides, and finely dispersed drug carrier substrates. These components are discussed in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present disclosure may also be delivered as microspheres for slow release in vivo. For example, the microspheres can be administered via intradermal injection of microspheres containing the drug that are slowly released subcutaneously (see Rao, J. Biomater Set Polym. ed. 7:623-645, 1995); administered as a biodegradable and injectable gel formulation (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or administered as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulation of the composition of the present disclosure can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, i.e., by using receptor ligands attached to the liposomes that bind to the cell's surface membrane protein receptors, resulting in endocytosis. By using liposomes, particularly where the liposomes carry receptor ligands specific for the target cells on their surface or are otherwise preferentially targeted to a particular organ, one can focus the delivery of the mTOR inhibitor to target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989.) In some embodiments, the mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) is delivered via nanoparticles.

[0104] Depending on the intended mode of administration, the mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) can be in solid, semisolid or liquid dosage form, such as, for example, injections, tablets, suppositories, pills, timed-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses and consistent with conventional pharmaceutical practice. Likewise, the mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) can be administered intravenously (both bolus and infusion), intraperitoneally, intrathecally, subcutaneously, and intramuscularly, and all using forms well known to those skilled in the art of pharmacy.

[0105] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) and a pharmaceutically acceptable carrier such as a) a diluent, e.g., purified water, a triglyceride oil (e.g., a hydrogenated or partially hydrogenated vegetable oil or a mixture thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (e.g., EPA or DHA) or an ester or triglyceride thereof or a mixture thereof, an omega-3 fatty acid or a derivative thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silicon dioxide, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; and b) a lubricant, e.g., silicon dioxide, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; For tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or sodium alginate), waxes and / or polyvinylpyrrolidone (if necessary); d) disintegrants, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants, such as Tween 80, Labrasol, HPMC, DOSS, caproyl909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifiers; and / or g) agents that promote absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0106] As used herein, the term "carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which is involved in carrying or transporting a pharmaceutical formulation from one organ or part of a subject's body to another organ or part of the body. Excipients should be selected based on compatibility and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, etc.

[0107] The term "pharmaceutically compatible carrier material" can include, for example, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium hydrogen phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, etc. See, for example, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

[0108] Liquid (particularly injectable) compositions can be prepared, for example, by dissolving, dispersing, etc. For example, an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) is dissolved in or mixed with a pharmaceutically acceptable solvent (e.g., such as water, saline, aqueous dextrose, glycerol, ethanol, etc.) to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicrons or serum proteins can be used to dissolve an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552).

[0109] The mTOR inhibitor (eg, a dual-site mTOR inhibitor, eg, RMC-5552) can also be formulated as a suppository, which can be prepared from a fatty emulsion or suspension; using a polyalkylene glycol such as propylene glycol as a carrier.

[0110] mTOR inhibitors (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) can also be administered in the form of liposome delivery systems (e.g., small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles). Liposomes can be formed from various phospholipids, containing cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, the membrane of the lipid component is hydrated with an aqueous solution of the drug to form a lipid layer that encapsulates the drug, as described in, e.g., U.S. Patent No. 5,262,564, the contents of which are hereby incorporated by reference.

[0111] mTOR inhibitors (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) can also be delivered by using monoclonal antibodies as a single carrier, and the disclosed compounds are coupled to the antibodies. The disclosed compounds can also be coupled to soluble polymers as targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the disclosed compounds can be coupled to a class of biodegradable polymers that can be used to achieve controlled release of drugs, such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic hydrogel block copolymers. In one embodiment, the disclosed compounds are not covalently bound to polymers (e.g., polycarboxylic acid polymers or polyacrylates).

[0112] Parenteral injection administration is generally for subcutaneous, intramuscular or intravenous injection and infusion. Injections can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolution in liquid prior to injection.

[0113] In some embodiments, the dose is administered via intravenous ("IV") infusion. In some embodiments, the dose is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours. In some embodiments, the dose is administered over about 0.5 hours, about 1 hour, about 1.5 hours, or about 2 hours. In some embodiments, the dose is administered over about 1 hour.

[0114] In some embodiments, the dosage is about 4 mg / week to about 25 mg / week, about 4 mg / week to about 14 mg / week, about 4 mg / week to about 12 mg / week, about 5 mg / week to about 25 mg / week, about 5 mg / week to about 14 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 6 mg / week to about 25 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week, About 7 mg / week to about 25 mg / week, about 7 mg / week to about 14 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 25 mg / week, about 8 mg / week to about 14 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week, and the dose is administered over about 0.5 hour to about 2 hours, over about 0.5 hour to about 1.5 hours, over about 0.5 hour to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours. In some embodiments, the dose is about 3 mg / week to about 25 mg / week, and is administered over about 0.5 hour to about 2 hours.

[0115] In some embodiments, the dosage is about 4 mg / week to about 25 mg / week, about 4 mg / week to about 14 mg / week, about 4 mg / week to about 12 mg / week, about 5 mg / week to about 25 mg / week, about 5 mg / week to about 14 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 6 mg / week to about 25 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about In some embodiments, the dosage is about 3 mg / week to about 25 mg / week, and is administered over about 1 hour.

[0116] In some embodiments, the dosage is about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 In some embodiments, the dosage is about 6 mg / week or about 8 mg / week and is administered over about 0.5 hour to about 2 hours, over about 0.5 hour to about 1.5 hours, over about 0.5 hour to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours. In some embodiments, the dosage is about 6 mg / week or about 8 mg / week and is administered over about 0.5 hour to about 2 hours.

[0117] In some embodiments, the dosage is about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week, or about 25 mg / week and is administered over about 0.5 hour, about 1 hour, about 1.5 hours, or about 2 hours. In some embodiments, the dosage is about 6 mg / week or about 8 mg / week and is administered over about 1 hour.

[0118] In some embodiments, the dose is administered once a week. For example, in some embodiments, a dose of about 3 mg / week to about 25 mg / week is administered via weekly intravenous infusion. In some embodiments, a dose of about 6 mg / week or about 8 mg / week is administered via weekly intravenous infusion. In some embodiments, the dose is administered once a week over about 0.5 hours to about 2 hours. In some embodiments, the dose is administered once a week over about 1 hour.

[0119] In some embodiments, the dosage is administered through multiple weekly administrations (e.g., multiple intravenous infusions). The sum of the mTOR inhibitor (e.g., dual-site mTOR inhibitor, e.g., RMC-5552) administered in multiple weekly administrations is the dosage. In some embodiments, the dosage is administered twice a week, three times a week, or four times a week. For example, in some embodiments, the dosage of about 3 mg / week to about 25 mg / week is administered in twice a week or three times a week intravenous infusions. In some embodiments, the dosage of about 6 mg / week or about 8 mg / week is administered in twice a week or three times a week intravenous infusions. In some embodiments, the dosage is administered twice a week or three times a week through about 0.5 hours to about 2 hours. In some embodiments, the dosage is administered twice a week or three times a week through each intravenous infusion of about 0.5 hours to about 1 hour.

[0120] As used herein, the term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; livestock, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc. In some embodiments, the subject is a human.

[0121] A "patient" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate (eg, monkey, chimpanzee, baboon, or rhesus monkey). "Patient" includes both humans and animals. Adverse Events

[0122] A challenge associated with many cancer drug treatments is administering a sufficient amount of the drug to a subject without causing intolerable side effects in the subject. Surprisingly, it has been discovered that providing and / or applying a mouthwash (e.g., tacrolimus mouthwash) to a subject and / or providing and / or applying ice to the oral cavity of a subject in combination with an mTOR inhibitor (e.g., a dual-site mTOR inhibitor (e.g., RMC-5552) and an allosteric mTOR inhibitor (e.g., everolimus, sirolimus, and albumin-bound sirolimus)) provides the ability to administer higher doses and / or results in reduced side effects.

[0123] In some embodiments, the methods of the present disclosure treat and / or prevent one or more side effects associated with the administration of an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus). Such side effects include, but are not limited to, anemia, nausea, mucositis (e.g., stomatitis), vomiting, diarrhea, fatigue, decreased appetite, hyponatremia, hyperglycemia, headache, dyspnea, and rash.

[0124] For example, using solutions (eg, mouthwashes) and / or borneol as described below, doses of mTOR inhibitors (eg, RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus) can be administered without causing intolerable stomatitis and / or mucositis.

[0125] As used herein, mucositis refers to inflammation and / or ulceration of the mucous membranes in the digestive tract, which is usually painful. Mucositis is often seen as an adverse reaction to chemotherapy and radiation therapy for cancer. Mucositis can occur anywhere in the gastrointestinal tract, but oral mucositis is particularly common and refers to inflammation and ulceration that occurs in the mouth. Given the prevalence of oral mucositis, sometimes the term "mucositis" is used to refer to "oral mucositis." Oral mucositis is also called stomatitis.

[0126] In some embodiments, the method further comprises providing and / or applying a solution (e.g., a mouthwash) to the subject and / or providing and / or applying ice to the subject's oral cavity. In some embodiments, the subject tolerates a higher dose of an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus) when a solution (e.g., a mouthwash) and / or ice is used compared to when no solution and / or ice is used.

[0127] In some embodiments, applying a solution (eg, a mouthwash) and / or ice is performed prior to administering an mTOR inhibitor (eg, a dual-site mTOR inhibitor, eg, RMC-5552). In some embodiments, the dosage of the dual-site mTOR inhibitor (e.g., RMC-5552) is about 6 mg / week to about 25 mg / week, about 6 mg / week to about 20 mg / week, about 6 mg / week to about 16 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 8 mg / week to about 25 mg / week, about 8 mg / week to about 20 mg / week, about 8 mg / week to about 16 mg / week, about 8 mg / week to about 14 mg / week, about 8 mg / week to about 12 mg / week, about 8 mg / week to about 10 mg / week, about 10 mg / week to about 25 mg / week, about 10 mg / week to about 20 mg / week, about 10 mg / week to about 16 mg / week, about 10 mg / week to about 14 mg / week, or about 10 mg / week to about 12 mg / week. In some embodiments, the dosage is about 10 mg / week to about 12 mg / week. In some embodiments, the dosage is about 10 mg / week to about 12 mg / week. In some embodiments, the dosage is about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week, or about 25 mg / week. In some embodiments, the dosage is about 10 mg / week. In some embodiments, the dosage is about 11 mg / week. In some embodiments, the dosage is about 12 mg / week. In some embodiments, the dosage is about 10 mg / week. In some embodiments, the dosage is about 11 mg / week. In some embodiments, the dosage is about 12 mg / week.

[0128] In some embodiments, the methods of the present disclosure further comprise administering a dexamethasone solution (eg, a mouthwash) to the subject.

[0129] In some embodiments, dexamethasone solution (e.g., mouthwash) comprises about 0.1 mg / 5 mL to about 1 mg / 5 mL, about 0.5 mg / 5 mL to about 5 mg / 5 mL, or about 0.5 mg / 5 mL to about 20 mg / 5 mL dexamethasone. In some embodiments, dexamethasone solution (e.g., mouthwash) comprises about 0.5 mg / 5 mL, about 1 mg / 5 mL, about 5 mg / 5 mL, about 10 mg / 5 mL, or about 20 mg / 5 mL dexamethasone. In some embodiments, dexamethasone solution (e.g., mouthwash) comprises about 0.5 mg / 5 mL dexamethasone.

[0130] In some embodiments, about 2.5 mL, about 5 mL, or about 10 mL of a dexamethasone solution (e.g., a mouthwash) is administered to a subject. In some embodiments, about 2.5 mL of the dexamethasone solution (e.g., a mouthwash) is administered to a subject. In some embodiments, a dexamethasone solution (e.g., a mouthwash) is administered 1, 2, 3, or 4 times daily.

[0131] In some embodiments, the methods of the present disclosure further include administering tacrolimus to the subject. For example, in some embodiments, tacrolimus is administered as a gel or as an ointment (e.g., as a 0.1% or as a 0.03% ointment), as a solution (e.g., a mouthwash), or as a tablet, pill, or capsule. Without being bound by any theory, it is believed that tacrolimus has the additional benefit of directly binding to the mTORC1 complex at the same binding site as the dual-site mTOR inhibitors disclosed herein (e.g., RMC-5552), blocking one of the two binding sites, or in the case of allosteric mTOR inhibitors (e.g., everolimus, sirolimus, and albumin-bound sirolimus), it is believed that tacrolimus advantageously competes with the allosteric mTOR inhibitors for presenting binding proteins (e.g., FKBP12), thereby selectively reducing the efficacy of the mTOR inhibitor in inhibiting mTOR signaling in the tissues of the subject that has been contacted with tacrolimus, and thereby reducing the adverse events induced by the mTOR inhibitors in the tissues.

[0132] In some embodiments, the method further comprises administering a tacrolimus solution (e.g., a mouthwash) to the subject. In some embodiments, the tacrolimus solution (e.g., a mouthwash) comprises about 0.1 mg / mL to about 1 mg / mL tacrolimus. In some embodiments, the tacrolimus solution (e.g., a mouthwash) comprises a solution (e.g., a mouthwash) of about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, or about 20 mg / mL. In some embodiments, the tacrolimus solution (e.g., a mouthwash) comprises about 0.5 mg / mL tacrolimus. In some embodiments, the tacrolimus solution (e.g., a mouthwash) comprises about 0.1 mg / mL tacrolimus.

[0133] In some embodiments, about 2.5mL, about 5mL or about 10mL of tacrolimus solution (e.g., mouthwash) is applied to the subject. In some embodiments, about 2.5mL of tacrolimus solution (e.g., mouthwash) is applied to the subject. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied 1, 2, 3 or 4 times daily. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied on the same day of mTOR inhibitor (e.g., dual-site mTOR inhibitor, such as RMC-5552) or before mTOR inhibitor (e.g., RMC-5552) is about to be applied. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied on the same day of intravenous infusion or before intravenous infusion. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied only on the same day of mTOR inhibitor (e.g., RMC-5552) or before mTOR inhibitor (e.g., RMC-5552) is about to be applied. In some embodiments, the tacrolimus solution (eg, mouthwash) is administered only on the day of the intravenous infusion or only immediately prior to the intravenous infusion.

[0134] In some embodiments, the method further comprises administering a combination solution (eg, a mouthwash) to the subject, wherein the combination solution (eg, a mouthwash) comprises dexamethasone and tacrolimus.

[0135] In some embodiments, the combined solution (e.g., mouthwash) comprises about 0.1 mg / 5 mL to about 1 mg / 5 mL, about 0.5 mg / 5 mL to about 5 mg / 5 mL, or about 0.5 mg / 5 mL to about 20 mg / 5 mL dexamethasone. In some embodiments, the dexamethasone solution (e.g., mouthwash) comprises about 0.5 mg / 5 mL, about 1 mg / 5 mL, about 5 mg / 5 mL, about 10 mg / 5 mL, or about 20 mg / 5 mL dexamethasone. In some embodiments, the combined solution (e.g., mouthwash) comprises about 0.5 mg / 5 mL dexamethasone.

[0136] In some embodiments, the combined solution (e.g., mouthwash) comprises about 0.1 mg / mL to about 1 mg / mL tacrolimus. In some embodiments, the combined solution (e.g., mouthwash) comprises about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, or about 20 mg / mL of tacrolimus. In some embodiments, the combined solution (e.g., mouthwash) comprises about 0.5 mg / mL tacrolimus. In some embodiments, the combined solution (e.g., mouthwash) comprises about 0.1 mg / mL tacrolimus.

[0137] In some embodiments, about 2.5mL of the combined solution (e.g., mouthwash) is applied to the subject. In some embodiments, the combined solution (e.g., mouthwash) is applied 1, 2, 3 or 4 times daily. In some embodiments, the combined solution (e.g., mouthwash) is applied on the same day of mTOR inhibitor (e.g., dual-site mTOR inhibitor, e.g., RMC-5552) or before mTOR inhibitor (e.g., dual-site mTOR inhibitor, e.g., RMC-5552) is applied. In some embodiments, the combined solution (e.g., mouthwash) is applied on the same day of intravenous infusion or before intravenous infusion. In some embodiments, the combined solution (e.g., mouthwash) is applied only on the same day of mTOR inhibitor (e.g., dual-site mTOR inhibitor, e.g., RMC-5552) or before mTOR inhibitor (e.g., dual-site mTOR inhibitor, e.g., RMC-5552) is applied. In some embodiments, the combination solution (eg, a mouthwash) is administered only on the day of the intravenous infusion or only immediately prior to the intravenous infusion of the mTOR inhibitor (eg, a dual-site mTOR inhibitor, eg, RMC-5552).

[0138] In some embodiments, the method for treating a subject with cancer further includes providing ice and / or applying ice to the subject's oral cavity. Ice can be applied before applying an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, such as RMC-5552), when applying an mTOR inhibitor (e.g., RMC-5552), after applying an mTOR inhibitor (e.g., RMC-5552), or some of the aforementioned combinations. In some embodiments, ice is applied for about 1 to about 60, about 1 to about 30, or about 1 to about 10 minutes before applying an mTOR inhibitor (e.g., RMC-5552), or for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes before applying an mTOR inhibitor (e.g., RMC-5552). In some embodiments, ice is applied during the application of an mTOR inhibitor (e.g., RMC-5552). In some embodiments, ice is applied for about 1 to about 60, about 1 to about 30, or about 1 to about 10 minutes after the mTOR inhibitor (e.g., RMC-5552) is applied, or ice is applied for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes after the mTOR inhibitor (e.g., RMC-5552) is applied. In some embodiments, ice is applied for about 10 minutes before the mTOR inhibitor (e.g., RMC-5552) is applied, during the mTOR inhibitor (e.g., RMC-5552), and after the mTOR inhibitor (e.g., RMC-5552) is applied. In some embodiments, ice is applied for about 1 to about 60, about 1 to about 30, or about 1 to about 10 minutes before intravenous infusion, or ice is applied for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes before intravenous infusion. In some embodiments, ice is applied during intravenous infusion. In some embodiments, ice is applied for about 1 to about 60, about 1 to about 30, or about 1 to about 10 minutes after the intravenous infusion, or ice is applied for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes after the intravenous infusion. In some embodiments, ice is applied for about 10 minutes before the intravenous infusion, during the intravenous infusion, and for about 10 minutes after the intravenous infusion.

[0139] In some embodiments, the present disclosure relates to a method for treating or preventing mucositis (e.g., stomatitis) in a subject in need thereof, the method comprising administering an effective amount of tacrolimus (e.g., a tacrolimus solution, such as a tacrolimus mouthwash). In some embodiments, mucositis (e.g., stomatitis) is associated with the administration of an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus). In some embodiments, a subject in need thereof is undergoing, has undergone, or will undergo treatment with an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus). In some embodiments, tacrolimus is administered as a gel or as an ointment (e.g., as a 0.1% or as a 0.03% ointment), as a solution (e.g., a mouthwash), or as a tablet, pill, or capsule. In some embodiments, tacrolimus is administered to a subject as a tacrolimus solution (e.g., a mouthwash). In some embodiments, tacrolimus solution (e.g., mouthwash) comprises about 0.1mg / mL to about 1mg / mL tacrolimus. In some embodiments, tacrolimus solution (e.g., mouthwash) comprises about 0.1mg / mL, about 0.5mg / mL, about 1mg / mL, about 5mg / mL, about 10mg / mL or about 20mg / mL solution (e.g., mouthwash). In some embodiments, tacrolimus solution (e.g., mouthwash) comprises about 0.5mg / mL tacrolimus. In some embodiments, tacrolimus solution (e.g., mouthwash) comprises about 0.1mg / mL tacrolimus. In some embodiments, about 2.5mL, about 5mL or about 10mL of tacrolimus solution (e.g., mouthwash) is applied to the subject. In some embodiments, about 2.5mL of tacrolimus solution (e.g., mouthwash) is applied to the subject. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied 1, 2, 3 or 4 times daily. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied on the day of mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus) or just before mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus) is applied. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied on the day of intravenous infusion or just before intravenous infusion. In some embodiments, tacrolimus solution (e.g., mouthwash) is applied only on the day of mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus) or just before mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and albumin-bound sirolimus) is applied.In some embodiments, the tacrolimus solution (eg, mouthwash) is administered only on the day of the intravenous infusion or only immediately prior to the intravenous infusion. Combination therapy

[0140] In some methods, an mTOR inhibitor (e.g., a dual-site mTOR inhibitor such as RMC-5552) is used in combination with one or more additional therapeutic agents. In these embodiments, the dosage of the one or more additional therapeutic agents may be reduced from their standard dosage (i.e., when they are administered alone).

[0141] The term "combination therapy" refers to a method of treatment, which includes administering to a subject at least two therapeutic agents, optionally as one or more pharmaceutical compositions. When used in combination therapy, an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, such as RMC-5552) can be administered simultaneously or separately with one or more therapeutic agents. This combination administration can include administering an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, such as RMC-5552) and the one or more therapeutic agents simultaneously in the same dosage form, administering simultaneously in a separate dosage form, and administering separately. That is, an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, such as RMC-5552) and any one or more therapeutic agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, such as RMC-5552) and one or more therapeutic agents can be administered simultaneously in a separate preparation. In another alternative, an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, such as RMC-5552) can be administered, and one or more therapeutic agents are subsequently administered, and vice versa. In some embodiments of the separate administration regimen, the mTOR inhibitor (eg, a dual-site mTOR inhibitor, eg, RMC-5552) and the one or more therapeutic agents are administered a few minutes apart, or a few hours apart, or a few days apart.

[0142] In some embodiments, an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) and one or more additional therapeutic agents are administered simultaneously or sequentially in either order. An mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) can be administered up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after one or more additional therapeutic agents.

[0143] The additional therapeutic agent can be administered in an effective amount. The additional therapeutic agent can be administered in a therapeutically effective amount. In some embodiments, for example, due to the additive or synergistic effect of combining two or more therapeutic agents, the effective amount of one or more additional therapeutic agents when used in a combination therapy may be lower than the therapeutic amount of the same therapeutic agent when used as a monotherapy.

[0144] When used in conjunction with a compound, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound sufficient to provide a desired biological result. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" of one or more additional therapeutic agents for therapeutic use is the amount of one or more additional therapeutic agents required to provide a clinically significant reduction in the disease.

[0145] In some embodiments, the method includes administering one or more additional therapeutic agents. In some embodiments, the method includes administering a therapeutically effective amount of additional therapeutic agents. In some embodiments, additional therapeutic agents are anticancer agents. In some embodiments, additional therapeutic agents are immunotherapeutic agents. In some embodiments, additional therapeutic agents are immuno-oncology agents. In some embodiments, additional therapeutic agents are anti-autoimmune disease agents. In some embodiments, additional therapeutic agents are anti-inflammatory disease agents. In some embodiments, additional therapeutic agents are anti-neurodegenerative disease agents. In some embodiments, additional therapeutic agents are anti-metabolic disease agents. In some embodiments, additional therapeutic agents are anti-cardiovascular disease agents. In some embodiments, additional therapeutic agents are anti-aging agents. In some embodiments, additional therapeutic agents are long-acting agents. In some embodiments, additional therapeutic agents are agents for treating or preventing transplant rejection. In some embodiments, additional therapeutic agents are agents for treating or preventing fungal infections. In some embodiments, additional therapeutic agents are immune system inhibitors. In some embodiments, additional therapeutic agents are mTOR regulators. In some embodiments, the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the additional therapeutic agent is an active site mTOR inhibitor. In some embodiments, the additional therapeutic agent is rapamycin. In some embodiments, the additional therapeutic agent is a rapamycin analog. In some embodiments, the additional therapeutic agent is an mTOR pathway inhibitor. In some embodiments, the additional therapeutic agent is a CDK4 / 6 inhibitor or an anti-PD1 / PD-L1, PI3K inhibitor. In some embodiments, the additional therapeutic agent is a RAS inhibitor.

[0146] In some embodiments, one or more additional therapeutic agents in the combination therapy comprises a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclomethasone, algestrone, amcinonide, beclomethasone, betamethasone, budesonide, cloprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, glycyrrhetinic acid, fluzacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone butyl, fluocortolone, fluorometholone, methylfluanilide acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocort, halcinonide, halobetasol propionate, propionate, halometasone, hydrocortisone, loteprednoletabonate, maprednione, medrysone, methylprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednididine, rimexolone, tixocortolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof.

[0147] Additional examples of therapeutic agents that can be used in combination therapy with an mTOR inhibitor (e.g., RMC-5552) include compounds described in U.S. Pat. Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Applications WO 01 / 37820, WO 01 / 32651, WO 02 / 68406, WO 02 / 66470, WO 02 / 55501, WO 04 / 05279, WO 04 / 07481, WO 04 / 07458, WO 04 / 09784, WO 02 / 59110, WO 99 / 45009, WO 00 / 59509, WO 99 / 61422, WO 00 / 12089 and WO 00 / 02871.

[0148] The therapeutic agent can be a biological agent (e.g., a cytokine (e.g., interferon or interleukin, such as IL-2)) for treating cancer or symptoms associated therewith. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. Antibody-drug conjugates are also included.

[0149] The therapeutic agent can be a T cell checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with the checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with the ligand of the checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of PDL-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of PDL-2 (e.g., PDL-2 / Ig fusion protein) (e.g., an inhibitory antibody or Fc fusion or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody (such as, for example, avelumab, durvalumab, atezolizumab, pidilizumab), JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or a checkpoint inhibitor disclosed in: Preus ser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirelumab, IPH2101, 1-7F9 and KW-6002.

[0150] The therapeutic agent can be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (Itilimab).

[0151] The therapeutic agent can be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, a non-peptide small molecule, or other compounds useful for treating cancer or symptoms associated therewith, collectively referred to as "anti-cancer agents"). The anti-cancer agent can be, for example, a chemotherapeutic agent or a targeted therapeutic agent.

[0152] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens and gonadotropin-releasing hormone analogs. Additional anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel. In some embodiments, the one or more additional therapeutic agents include two or more anticancer agents. The two or more anticancer agents can be used in a mixture to be administered in combination, or administered separately. Suitable dosing regimens for combined anticancer agents are known in the art and described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0153] Other non-limiting examples of anticancer agents that can be used in the combination therapies described herein include (imatinib mesylate); (carfilzomib); (bortezomib);Casodex (bicalutamide); (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; polyacetyl groups (especially bullatacin and bullatacinone); e)); camptothecins (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adolesin, carzelesin and biszelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; sarcodictin A; A); spongistatin; nitrogen mustards (e.g., chlorambucil), naphthyl nitrogen mustard, chlorophosphamide, estramustine, ifosfamide, dichloromethyl diethylamine, mechlorethamine oxide hydrochloride, melphalan, nembixin, phenesterine, phenyl mustard, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins, such as calicheamicin gamma ll and calicheamicin omega ll (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins, such as danimycin A; bisphosphonates, such as clodronate; esperamicins;New carcinostomycin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomysin, actinomycin, authramycin, azoserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, masiromycin marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid, nogamycin, olive mycin, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptomycin, streptozotocin, tuberculocin, ubenimex, zoloft, doxycycline; antimetabolites such as methotrexate and 5-fluorouracil (5-FU) ); folic acid analogs, such as denopterin, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as captestosterone, dromostanolone propionate, epitiostanol, mesandrostane, testolactone; antiadreners, such as aminoglutethimide, mitotane, triptostane; folic acid supplements, such as folic acid; aceglucuronolide; aldophosphamide glycosides; aminolevulinic acid acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colcemid; diaziquone; elfomithine; eliptamide; epothilones, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansines, such as maytansine and ansamitocin; mitoguanidine, mitoxantrone; mopidamol; nitracrine; pentostatin;Phenemat; pirarubicin; losoxantrone; podophyllinic acid; 2-acetylhydrazine; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, OR, USA); aprotinin; rhizoxin; siroxan; spirogermanium; tenuazonic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; trichothecenes, such as T-2 toxin, verracurin A, roridin A, and anguidine; urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromomannitol; pipobroman; gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as (paclitaxel), (Polyoxyethylene hydrogenated castor oil, albumin engineered paclitaxel nanoparticle formulation) and (docetaxel); chlorambucil; tamoxifen (Nolvadex TM );raloxifene;aromatase inhibitory 4(5)-aromatase inhibitory;4-hydroxytamoxifen;trioxifene;keoxifene;LY 117018;onapristone;toremifene Flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamicins; capecitabine (e.g., ); and a pharmaceutically acceptable salt of any one of the foregoing.

[0154] Additional non-limiting examples of anticancer agents that can be used in the combination therapies disclosed herein include trastuzumab Bevacizumab Cetuximab Rituximab ABVD, avicine, abagovomab, acridinium carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, aminonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agents (e.g., cell cycle nonspecific antineoplastic agents and other antineoplastic agents described herein), anti-tumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, bilicodal, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, scutellarin, elsamitrucin, enocitabine, eribulin, exitecan, exisulin, ferrugol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolecarbazole, irofulven, laniquidar, larotate axel), lenalidomide, lucanthone, lortotecan, mafosfamide, mitozolamide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V V), swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatinium tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

[0155] Other non-limiting examples of anticancer agents that can be used in the combination therapies described herein include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin / actinomycin D), daunomycin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycins, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and removes cells that cannot synthesize asparagine themselves), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., methyl mustard, cyclophosphamide, and the analog melphalan). ) and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abemaciclib, ribociclib, palbociclib, seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638 and S CH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites (such as folic acid analogs), pyrimidine analogs (e.g., fluorouracil, azathiouracil, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), Aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, amine glutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), KSP (Eg5) inhibitors (e.g.,Array 520), DNA binding agents (e.g., ), PI3K inhibitors such as PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3Kδ and γ inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogens) and hormone agonists (such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38 MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), Aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra TM ), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0156] In some embodiments, the anticancer agent is selected from dichloromethane, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Sorafenib or any analog or derivative variant of the foregoing.

[0157] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab and pertuzumab Small molecule tyrosine kinase inhibitors, such as gefitinib Erlotinib pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; ), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0158] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib, brigatinib, entrectinib, ensartinib (X-396), lorlatinib, ASP3026, CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005 and AP26113. Other examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0159] In some embodiments, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., a SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, or BBP-398), a SOS1 inhibitor (e.g., BI-1701963, BI-3406, or RMC-5845), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, or an AKT inhibitor). In some embodiments, the anticancer agent is JAB-3312.

[0160] In some embodiments, the therapeutic agent that can be combined with an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) is an inhibitor of the MAP kinase (MAPK) pathway (or "MAPK inhibitor"). MAPK inhibitors include, but are not limited to, one or more of the MAPK inhibitors described in Cancer (Basel) 2015 Sep; 7(3): 1758-1784. In some embodiments, the MAPK inhibitor can be selected from one or more of the following: trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (described by Roche in PLoS One. 2014 Nov 25; 9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1; 17(5):989-1000). The MAPK inhibitor may be PLX8394, LXH254, GDC-5573 or LY3009120.

[0161] In some embodiments, the anticancer agent is a destroyer or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) September 2015; 7(3): 1758-1784. For example, PI3K / AKT inhibitors may be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0162] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0163] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors and immunotherapy. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor, such as afatinib.

[0164] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0165] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful antibody inhibitors of EGFR include cetuximab Panitumumab Zalutumumab, nimotuzumab and matuzumab. Additional antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation of its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in: Modjtahedi et al., Br. J. Cancer 1993, 67: 247-253; Teramoto et al., Cancer 1996, 77: 639-645; Goldstein et al., Clin. Cancer Res. 1995, 1: 1311-1318; Huang et al., 1999, Cancer Res. 15: 59 (8): 1935-40; and Yang et al., Cancer Res. 1999, 59: 1236-1243. The EGFR inhibitor may be a monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment thereof having binding specificity.

[0166] Small molecule EGFR antagonists include gefitinib Erlotinib and lapatinib See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics in Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations in Lung Cancer Correlation with Clinical Response to Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO 96 / 33980; U.S. Pat. No. 5,747,498; WO 96 / 30347; EP 0787772; WO 97 / 30034; WO 97 / 30044; WO 97 / 38994; WO 97 / 49688; EP 837063; WO 98 / 02434; WO 97 / 38983; WO 95 / 19774; WO 95 / 19970; WO 97 / 13771; WO 98 / 02437; WO 98 / 02438; WO 97 / 32881; DE 19629652;WO98 / 33798;WO 97 / 32880;WO 97 / 32880;EP 682027;WO 97 / 02266;WO 97 / 27199;WO 98 / 07726;WO 97 / 34895;WO 96 / 31510;WO WO 98 / 14449; WO 98 / 14450; WO 98 / 14451; WO 95 / 09847; WO 97 / 19065; WO 98 / 17662; 99 / 35132; WO 99 / 07701; and WO 92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12): 1599-1625.

[0167] MEK inhibitors include but are not limited to pimsertinib, selumetinib, cobimetinib Trametinib and bimetinib In some embodiments, the MEK inhibitor targets a MEK mutation that is a class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0168] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO 06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941, and described in WO 09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO 06 / 122806); (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinopyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride) (available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide) (available from Axon Medchem); AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione) (available from Axon Medchem); Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one) (available from Axon Medchem); XL-765 and XL-147.Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0169] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91: 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3-methanol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Suppl):3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0170] BRAF inhibitors that can be used in combination with mTOR inhibitors (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) include, for example, vemurafenib, dabrafenib, and encofenib. BRAF may comprise Class 3 BRAF mutations. In some embodiments, Class 3 BRAF mutations are selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E.

[0171] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance not only to traditional chemotherapy, but also to targeted therapeutics including BCL-2 inhibitors (such as ABT-263).

[0172] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that promotes a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive autoinhibitory conformation that is stabilized by a binding network containing residues from both the N-SH2 and PTP domains. The catalytic site is exposed by stimulation by, for example, cytokines or growth factors acting through receptor tyrosine kinases (RTKs), resulting in enzymatic activation of SHP2.

[0173] SHP2 participates in signal transduction via RAS-mitogen-activated protein kinase (MAPK), JAK-STAT or phosphoinositide 3-kinase-AKT pathways. Mutations in the PTPN11 gene have been identified in several human developmental diseases (such as Noonan Syndrome and Leopard Syndrome) and human cancers (such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung and colon cancers), and subsequently mutations in SHP2. Some of these mutations destabilize the autoinhibitory conformation of SHP2 and promote autoactivation of SHP2 or enhanced activation driven by growth factors. Therefore, SHP2 represents an attractive target for the development of new therapies for the treatment of a variety of diseases including cancer. It has been shown that SHP2 inhibitors (e.g., RMC-4550 or SHP099) combined with RAS pathway inhibitors (e.g., MEK inhibitors) inhibit proliferation of multiple cancer cell lines (e.g., pancreatic cancer, lung cancer, ovarian cancer, and breast cancer) in vitro. Therefore, combination therapy involving SHP2 inhibitors and RAS pathway inhibitors may be a general strategy for preventing tumor resistance in a wide range of malignancies.

[0174] Intellectual and non-restrictive examples of SHP2 suppression in this area: Chen et al. MolPharmacol.2006,70,562; Sarver et al., J.Med.Chem.2017,62,1 793; 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO2022234409, WO 2022208408, WO 2022207924, WO 2022167682, WO 2022166844, WO2022161222, WO 2022156765, WO 2022135568, WO 2022089406, WO 2022089389, WO2022063190, WO 2022043685, WO 2022042331, WO 2022033430, WO 2022033430, WO2022017444, WO 2022007869, WO 2021259077, WO 2021249449, WO 2021249057, WO2021244659, WO 2021218755, WO 2021281752, WO 2021197542, WO 2021176072, WO2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO2021143680, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO2021018287、WO2020259679、WO 2020249079、WO 2020210384、WO 2020201991、WO 2020181283、WO2020177653、WO 2020165734、WO 2020165733、WO 2020165732、WO 2020156243、WO2020156242、WO 2020108590、WO 2020104635、WO 2020094104、WO 2020094018、WO2020081848、WO 2020073949、WO 2020073945、WO 2020072656、WO 2020065453、WO2020065452、WO 2020063760、WO 2020061103、WO 2020061101、WO 2020033828、WO2020033286、WO 2020022323、WO 2019233810、WO 2019213318、WO 2019183367、WO2019183364、WO 2019182960、WO 2019167000、WO 2019165073、WO 2019158019、WO2019152454、WO 2019051469、WO 2019051084、WO 2018218133、WO 2018172984、WO2018160731、WO 2018136265、WO 2018136264、WO 2018130928、WO 2018129402、WO2018081091、WO 2018057884、WO 2018013597、WO 2017216706、WO 2017211303、WO2017210134、WO 2017156397、WO 2017100279、WO 2017079723、WO 2017078499、WO2016203406、WO 2016203405、WO 2016203404、WO 2016196591、WO 2016191328、WO2015107495、WO 2015107494、WO 2015107493、WO 2014176488、WO 2014113584、US20210085677、US 10858359、US 10934302、US 10954243、US 10988466、US 11001561、US11033547、US11034705、US 11044675、US 11179397、CN 115677661、CN 115677660、CN115611869、CN 115521305、CN 115490697、CN 115466273、CN 115394612、CN 115304613、CN115304612、CN 115300513、CN 115197225、CN 114957162、CN 114920759、CN 114716448、CN114671879、CN 114539223、CN 114524772、CN 114213417、CN 114163457, CN 113896710, CN113248521, CN 113248449, CN 113135924, CN 113024508, CN112920131, CN 112823796, CN112402385, CN 111848599, CN 111704611, CN 111265529 and CN 108113848, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs or tautomers thereof, each of which is incorporated herein by reference in its entirety.

[0175] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, for example, a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor targeting a cysteine ​​residue (C333) located outside the phosphatase active site. In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630, the structure of which is shown below:

[0176] In some embodiments, the SHP2 inhibitor is JAB-3068, JAB-3312, RLY-1971, ERAS-601, or BBP-398.

[0177] In some embodiments, the additional therapeutic agent is selected from a HER2 inhibitor, a SHP2 inhibitor, a CDK4 / 6 inhibitor, a SOS1 inhibitor, and a PD-L1 inhibitor. See, e.g., Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575: 217 (2019).

[0178] Proteasome inhibitors include but are not limited to carfilzomib Bortezomib and oprozomib.

[0179] Immunotherapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents).

[0180] Immunomodulators (IMiDs) are a class of immunomodulatory drugs (drugs that modulate immune responses) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0181] Exemplary anti-PD-1 antibodies and methods of use thereof are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO 06 / 121168A1), and as described elsewhere herein.

[0182] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Pat. No. 6,111,090, U.S. Pat. No. 8,586,023, WO 2010 / 003118, and WO 2011 / 090754; or anti-GITR antibodies such as those described in U.S. Pat. No. 7,025,962, EP 1947183, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, U.S. Pat. No. 7,618,632, EP 1866339, and WO 2011 / 028683, WO 2013 / 039954, WO 05 / 007190, WO 07 / 133822, WO 05 / 055808, WO 99 / 40196, WO 01 / 03720, WO 99 / 20758, WO06 / 083289, WO 05 / 115451 and WO2011 / 051726.

[0183] Another example of a therapeutic agent that can be used in combination with an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof prepared by in vitro synthesis. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, can act to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or prevent cell growth. In some embodiments, the one or more additional therapeutic agents include anti-angiogenic agents.

[0184] Anti-angiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96 / 33172, WO 96 / 27583, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 99007675, EP 0606046, EP 0780386, EP 1786785, EP 1181017, EP 0818442, EP1004578 and US20090012085 and U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those with little or no activity to inhibit MMP-1. More preferred are those that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555 and RS13-0830.

[0185] Additional exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF (e.g., bevacizumab), or soluble VEGF receptors or their ligand binding regions (e.g., VEGF-TRAP TM ) and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto) (e.g., (panitumumab), erlotinib ), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind to them or to their receptors (e.g., Tie2 / Tek)) and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind to them). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US 2003 / 0162712; US 6,413,932), anti-TWEAK agents (e.g., antibodies or antigen binding regions that specifically bind to them, or soluble TWEAK receptor antagonists; see US 6,727,225), ADAM disintegrin domains for antagonizing the binding of integrins to their ligands (US2002 / 0042368), specifically binding anti-eph receptor or anti-ephrin antibodies or antigen binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of their patent families), and anti-PDGF-BB antagonists (e.g., specifically binding antibodies or antigen binding regions), as well as antibodies or antigen binding regions that specifically bind to PDGF-BB ligands and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto). Other anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA);CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); maspin (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); second-generation α5β3 integrin MAb (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA andSanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI21 and BPI-derived antiangiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Cilengitide (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA);Endostatin (Boston Childrens' Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); vatalanib (pINN) (Novartis, Switzerl and Schering AG, Germany); tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthorrhizol (Yonsei University, South Korea); gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX478 (ProlX, USA); METASTATIN (EntreMed, USA); troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE941 (Aeterna, Canada); angiogenesis vaccine (EntreMed, USA); urokinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); angustin (InKine, USA);A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); drug delivery system, intraocular 2-methoxyestradiol; anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-α inhibitor; SU 11248 (Pfizer, USA and SUGEN, USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); GFB 116 (South Florida University, USA, and Yale University, USA); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA); CV 247 (IvyMedical, UK); CKD 732 (Chong KunDang, South Korea);Irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (Genaera, USA); RPI 4610 (Sirna, USA); heparanase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); ofHealth, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); Tumstatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0186] Additional examples of therapeutic agents that can be used in combination with mTOR inhibitors (e.g., RMC-5552) include agents (e.g., antibodies, antigen binding regions, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen binding regions that specifically bind to its receptor c-Met.

[0187] Another example of a therapeutic agent that can be used in combination with an mTOR inhibitor (e.g., RMC-5552) is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil TM), bafilomycin A1, 5-amino-4-imidazolecarboxamide ribonucleoside (AICAR), okadaic acid, autophagy-inhibiting algae toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels (such as adenosine, LY204002, N6-mercaptopurine ribonucleoside and vinblastine). In addition, antisense or siRNA that inhibits protein expression can also be used, and the protein includes but is not limited to ATG5 (which is involved in autophagy). In some embodiments, the one or more additional therapeutic agents include an autophagy inhibitor.

[0188] Another example of a therapeutic agent that can be used in combination with an mTOR inhibitor (eg, RMC-5552) is an anti-neoplastic agent. In some embodiments, the one or more additional therapeutic agents include an anti-neoplastic agent. Non-limiting examples of anti-tumor agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate), DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT, diclofenac, interferon alpha, daunomycin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate phosphate), exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphatephosphate), formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid acid), idarubicin, imiquimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-Nl, interferon alpha-n3, composite interferon-1, natural interferon alpha, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate sulfate), letrozole, interferon alpha, leuprolide, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguanidine, dibromomannitol, mitoxantrone, morasporastin ( molgramostim), nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon α-2b, pentosan polysulfate sodiumpolysulfate sodium), pentostatin, picibanil, birubicin, rabbit anti-thymocyte polyclonal antibody, peginterferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, etidronate rhenium Re 186, RII retinamide, rituximab, romurtide, samarium 153Sm lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131), trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, native tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, spalfosic acid, SRL172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New YorkUniversity), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0189] Additional examples of therapeutic agents that can be used in combination with mTOR inhibitors (eg, RMC-5552) include ipilimumab Tremelimumab; galiximab; nivolumab, also known as BMS-936558 Pembrolizumab Avelumab AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 MSB0010718C; AMP224; adalimumab ado-trastuzumabemtansine Aflibercept Alemtuzumab Basiliximab Belimumab Basiliximab Belimumab Brentuximab vedotin Canakinumab Certolizumab pegol Daclizumab Daratumumab Denosumab Eculizumab Efalizumab Gemtuzumab ozogamicin Golimumab Ibritumomab tiuxetan infliximab Motavizumab Natalizumab Obinutuzumab Ofatumumab Omalizumab Palivizumab Pertuzumab Pertuzumab Pertuzumab Ranibizumab Raxibacumab Tocilizumab Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 Ustekinumab AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0190] As required for the treatment of the condition, the effective dose of the ALK inhibitor when used for the indicated effect is in the range of about 0.5 mg to about 5000 mg. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed compound, or within the range of one amount to another amount in the dosage list. In some embodiments, the composition is in the form of a tablet that can be scored.

[0191] As required for the treatment of the condition, the effective dose of the EGFR inhibitor when used for the indicated effect is in the range of about 0.5 mg to about 5000 mg. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed compound, or within the range of one amount to another amount in the dosage list. In some embodiments, the composition is in the form of a tablet that can be scored.

[0192] As required for the treatment of the condition, the effective dose of the MEK inhibitor when used for the indicated effect is in the range of about 0.05 mg to about 5000 mg. Compositions for in vivo or in vitro use may contain about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed compound, or in the range of one amount to another amount in the dosage list. In some embodiments, the composition is in the form of a tablet that can be scored.

[0193] In some embodiments, at least one additional therapeutic agent is a RAS inhibitor. The terms "RAS inhibitor" and "[a]RAS inhibitor" are used interchangeably and refer to any inhibitor targeting a RAS protein. In various embodiments, these terms include RAS(OFF) and RAS(ON) inhibitors, such as, for example, KRAS(OFF) and KRAS(ON) inhibitors disclosed herein. The term "RAS(OFF) inhibitor" refers to any inhibitor that binds to a RAS protein in the "OFF" position to which its GDP is bound, as further defined herein. The term "RAS(ON) inhibitor" refers to any inhibitor that binds to a RAS protein in the "ON" position to which its GDP is bound, as further defined herein. In some embodiments, a RAS inhibitor has a molecular weight of less than 700Da. In some embodiments, the RAS inhibitor is selected from AMG 510, MRTX1257, JNJ-74699157 (ARS-3248), LY3537982, LY3499446, ARS-853, ARS-1620, GDC-6036, BPI-421286, JDQ443, JAB-21000, JAB-22000, JAB-23000, RSC-1255, ERAS-3490, D-1553, JAB-21822, GH-35, ICP-915, IBI351 and BI1823911. The RAS inhibitor can be a RAS vaccine, or another treatment modality designed to directly or indirectly reduce the oncogenic activity of RAS.

[0194] The terms "RAS pathway" and "RAS / MAPK pathway" are used interchangeably herein and refer to a signal transduction cascade downstream of various cell surface growth factor receptors, in which activation of RAS (and its various isoforms and alleles) is a central event that drives a variety of cellular effector events that determine proliferation, activation, differentiation, mobilization, and other functional properties of cells. SHP2 transmits positive signals from growth factor receptors to the RAS activation / inactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that load GTP onto RAS to produce functionally active GTP-bound RAS and GTP-accelerating proteins (GAPs, such as NF1) that promote signal termination by converting GTP to GDP. The GTP-bound RAS generated by this cycle transmits the necessary positive signal to a series of serine / threonine kinases, including RAFs and MAP kinases, from which other signals are emitted to a variety of cellular effector functions.

[0195] In some embodiments, the RAS inhibitor targets KRAS, NRAS or HRAS. In some embodiments, the RAS inhibitor is a RAS mutant-specific inhibitor. In some embodiments, the RAS mutant is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R and combinations thereof; and (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof.

[0196] Mutations at these positions can give rise to RAS-driven tumors.

[0197] Methods for detecting mutations in KRAS, HRAS or NRAS nucleotide sequences are well known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay and microarray analysis. In some embodiments, the G12C KRAS, HRAS or NRAS mutation of the sample is evaluated by real-time PCR. In real-time PCR, a specific fluorescent probe for KRAS, HRAS or NRASG12C mutation is used. When there is a mutation, the probe binds and fluorescence is detected. In some embodiments, for example, a direct sequencing method of a specific region (e.g., exon 2 and / or exon 3) in a KRAS, HRAS or NRAS gene is used to identify KRAS, HRAS or NRAS G12C mutations. This technique will identify all possible mutations in the sequenced region.

[0198] Methods for detecting mutations in KRAS, HRAS or NRAS proteins are well known to those skilled in the art. These methods include, but are not limited to, using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing to detect KRAS, HRAS or NRAS mutants.

[0199] Methods for determining whether a tumor or cancer comprises G12C or other KRAS, HRAS or NRAS mutations can use various samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0200] In some embodiments, at least one additional therapeutic agent is a RAS(OFF) inhibitor. In various embodiments, at least one additional therapeutic agent is a KRAS(OFF) inhibitor (e.g., any one or more KRAS(OFF) inhibitors disclosed herein or known in the art). In some embodiments, at least one additional therapeutic agent is a KRAS(OFF) inhibitor. G12C (OFF) inhibitors (e.g., KRAS disclosed herein or known in the art) G12C (OFF) inhibitors). In some embodiments, at least one additional therapeutic agent is AMG 510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, at least one additional therapeutic agent is selected from AMG 510 and MRTX849. In some embodiments, the therapeutic agent is AMG 510. In some embodiments, the therapeutic agent is MRTX849. In various embodiments, at least one additional therapeutic agent is an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552), and one additional therapeutic agent is a KRAS G12C Inhibitor.

[0201] As used herein, the term "RAS (OFF) inhibitor" refers to an inhibitor that targets, i.e., selectively binds or inhibits an inactive state of RAS bound to GDP (e.g., selectively compared to an active state of RAS bound to GTP). Inhibition of RAS in an inactive state bound to GDP includes, for example, isolating an inactive state by inhibiting the exchange of GDP with GTP, thereby inhibiting RAS from adopting an active conformation. In some embodiments, RAS (OFF) inhibitors may also bind or inhibit RAS in an active state bound to GTP (e.g., having a lower affinity or inhibition constant than RAS in an inactive state bound to GDP). In some embodiments, RAS (OFF) inhibitors have a molecular weight of less than 700 Da. The term "KRAS (OFF) inhibitor" refers to any inhibitor that binds to KRAS in the "OFF" position of its GDP binding. Reference to the term KRAS (OFF) inhibitor includes, for example, AMG510, MRTX849, JDQ443, and MRTX1133. In some embodiments, KRAS (OFF) inhibitors are selected from AMG 510 and MRTX849. In some embodiments, the KRAS (OFF) inhibitor is AMG 510. In some embodiments, the KRAS (OFF) inhibitor is MRTX849. In some embodiments, the RAS (OFF) inhibitor is selected from sotolacib (AMG 510), adagracib (MRTX849), MRTX1257, JNJ-74699157 (ARS-3248), LY3537982, LY3499446, ARS-853, ARS-1620, GDC-6036, JDQ443, BPI-421286, JAB-21000, RSC-1255, ERAS-3490, D-1553, JAB-21822, GH-35, ICP-915, IBI351 and BI1823911. In some embodiments, reference to the term RAS(OFF) inhibitor includes any such RAS(OFF) inhibitor disclosed in any of the following patent applications: WO 2023287896, WO2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO2023283213, WO 2023280960, WO 2023280280, WO 2023280136, WO 2023280026, WO2023278600, WO 2023274383, WO 2023274324, WO 2023034290, WO 2023020523, WO 2023020521, WO 2023020519、WO2023020518, WO 2023018812, WO 2023018810, WO 2023018809, WO 2023018699, WO 2023015559, WO 2023014979, WO 2023014006, WO2023010121, WO 2023009716, WO 2023009572, WO 2023004102, WO 2023003417, WO2023001141, WO 2023001123, WO 2022271923, WO 2022271823, WO 2022271810, WO2022271658, WO 2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO2022265974, WO 2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO2022237815, WO 2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO2022223037, WO 2022221739, WO 2022221528, WO 2022221386, WO 2022216762、WO2022192794、WO 2022192790、WO 2022188729、WO 2022187411、WO 2022184178、WO2022173870、WO 2022173678、WO 2022135346、WO 2022133731、WO 2022133038、WO2022133345、WO 2022132200、WO 2022119748、WO 2022109485、WO 2022109487、WO2022098625、WO 2022095960、WO 2022093856、WO 2022089219, WO 2022087624, WO 2022087375, WO 2022087371, WO 2022083616, WO 2022083569, WO 2022081655, WO 2022076917, WO 2022072783, WO 2022066805, WO 2022066646, WO 2022063297, WO 2022061251, WO2022056307, WO 2022052895, WO 2022048545, WO2022047093, WO 2022042630, WO2022040469, WO 2022037631, WO 2022037560, WO 2022031678, WO 2022028492, WO2022028346, WO 2022026726, WO 2022026723, WO 2022015375, WO 2022002102, WO2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO2021185233, WO 2021180181、WO 2021175199、2021173923、WO 2021169990、WO2021169963、WO 2021168193、WO 2021158071、WO 2021155716、WO 2021152149、WO2021150613、WO 2021147967、WO 2021147965、WO 2021143693、WO 2021142252、WO2021141628、WO 2021139748、WO 2021139678、WO 2021129824、WO 2021129820, WO2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO2021121367, WO 2021121330, WO 2021088458, WO 2021086833, WO 2021085653, WO2021084765, WO 2021081212, WO 2021058018, WO 2021057832, WO2021055728, WO2021031952, WO 2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO2020234103, WO 2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO2020118066, WO 2020113071, WO 2020106647, WO 2020102730, WO 20201736, WO2020097537, WO 2020086739, WO 2020081282, WO 2019150305、WO 2019110751、WO 2019099524、WO 2019051291、WO 2018218070、WO2018218071、WO 2018218069、WO 2018217651、WO 2018206539、WO 2018143315、WO2018140600、WO 2018140599、WO 2018140598、WO 2018140514、WO 2018140513、WO2018140512、WO 2018119183、WO 2018112420、WO 2018068017、WO 2018064510、WO2017201161、WO 2017172979、WO 2017100546、WO 2017087528、WO 2017058807、WO2017058805、WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, CN114437084, CN114195788、CN 114437107、CN 114409653、CN 114380827、CN 114195804、CN114057776、CN 114057744、CN 114057743、CN 113999226、CN 113980032、CN 113980014、CN113960193、CN 113929676、CN 113754653、CN 113683616、CN 113563323、CN 113527299、CN113527294、CN 113527293、CN 113493440、CN 113429405, CN 113248521, CN 113321654, CN113087700, CN 113024544, CN 113004269, CN 112920183, CN 112778284, CN 112390818, CN112390788, CN 112300196, CN 112300194, CN 112300173, CN 112225734, CN 112142735, CN112110918, CN 112094269, CN 112047937 and CN 109574871, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof, each of which is incorporated herein by reference in its entirety. "AMG 510" and "MRTX849" referred to herein refer to the following compounds:

[0202] In some embodiments, at least one additional therapeutic agent is a RAS(ON) inhibitor. In various embodiments, at least one additional therapeutic agent is a KRAS(ON) inhibitor (e.g., any one or more KRAS(ON) inhibitors disclosed herein or known in the art). In some embodiments, at least one additional therapeutic agent is RMC-6236 (RAS MULTI (ON) inhibitor), RMC-6291 (KRAS G12C (ON) inhibitor), RMC-9805 (KRAS G12D (ON) inhibitor), RMC-8839 (KRAS G13C (ON) inhibitor), RMC-0708 (KRAS Q61H (ON) inhibitor) or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, at least one additional therapeutic agent is a KRAS G12C(ON) inhibitors (e.g., KRAS disclosed herein or known in the art) G12C In some embodiments, KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0203] As used herein, the term "RAS (ON) inhibitor" refers to an inhibitor that targets, i.e., selectively binds or inhibits an active state of RAS bound to GTP (e.g., selectively compared to an inactive state of RAS bound to GDP). The inhibition of the active state of RAS bound to GTP includes, for example, the inhibition of oncogenic signaling from an active state of RAS bound to GTP. In some embodiments, a RAS (ON) inhibitor is an inhibitor of RAS in an active state that selectively binds and inhibits GTP-bound. In some embodiments, a RAS (ON) inhibitor can also bind or inhibit an inactive state of RAS bound to GDP (e.g., having a lower affinity or inhibition constant than an active state of RAS bound to GTP). In some embodiments, a RAS (ON) inhibitor has a molecular weight between 800 and 1100 Da, including end values. The term "KRAS (ON) inhibitor" refers to any inhibitor that binds to KRAS at the "ON" position of its GDP binding. The term RAS(ON) inhibitor includes, but is not limited to, any one or more RAS(ON) inhibitors selected from the RAS(ON) inhibitors disclosed in PCT / US2023 / 060288, 2023060253, WO 2022235870, WO 2022235864, WO 2022060836, WO2021257736, WO 2021091982, WO 2021091967 or WO 2021091956, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof, or a combination of any such RAS(ON) inhibitors. Indications

[0204] The present disclosure provides methods for treating a disease or disorder mediated by mTOR in a subject in need thereof. The present disclosure also provides methods for preventing a disease or disorder mediated by mTOR in a subject in need thereof. The present disclosure also provides methods for reducing the risk of a disease or disorder mediated by mTOR in a subject in need thereof.

[0205] In some embodiments, the disease is cancer or an immune-mediated disease. In some embodiments, the cancer is selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphoma, gastric cancer, kidney cancer, renal cancer, liver cancer, ovarian cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulvar cancer, prostate cancer, penis cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal stromal tumors, and neuroendocrine tumors. In some embodiments, the disorder is cirrhosis of the liver. In some embodiments, immune-mediated diseases are selected from the drug resistance caused by transplantation of heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, duodenum, small intestine, or islet cells; Graft-versus-host disease caused by bone marrow transplantation; Rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis. In certain embodiments, the disease is tuberous sclerosis complex (TSC). In certain embodiments, the disease is pancreatic neuroendocrine tumor (PNET), mantle cell lymphoma (MCL), colorectal cancer or intestinal cancer (CRC), uterine cancer, ovarian cancer, bladder cancer, genitourinary tract cancer, or renal cell carcinoma (RCC).

[0206] In some embodiments, the cancer is selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphoma, gastric cancer, kidney cancer, renal cancer, liver cancer, ovarian cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, blood proliferative disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulvar cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal stromal tumors, and neuroendocrine tumors. In some embodiments, the disorder is cirrhosis of the liver. In certain embodiments, the disease is tuberous sclerosis complex (TSC). In certain embodiments, the disease is pancreatic neuroendocrine tumor (PNET), mantle cell lymphoma (MCL), colorectal cancer or intestinal cancer (CRC), uterine cancer, ovarian cancer, bladder cancer, genitourinary tract cancer, or renal cell carcinoma (RCC).

[0207] In some embodiments, cancers include human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, and the like, including solid and lymphomas, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, gliomas, esophageal cancer, and liver cancer (including hepatocarcinoma), lymphomas (including B-acute lymphoblastic lymphoma, non-Hodgkin lymphoma (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma), leukemias (including AML, ALL, and CML), or multiple myeloma. In certain embodiments, the disease is multiple myeloma. In certain embodiments, the disease is breast cancer. In certain embodiments, the disease is triple-negative breast cancer.

[0208] In some embodiments, cancer includes cancer, neoplasm or malignant tumor found in mammals (e.g., humans), including leukemia, carcinoma and sarcoma. Exemplary cancers that can be treated with the compounds or methods provided herein include prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples may include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0209] In some embodiments, the disease is a leukemia. The term "leukemia" refers broadly to a progressive malignant disease of the hematopoietic organs and is generally characterized by abnormal proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are generally clinically classified based on: (1) the duration and characteristics of the acute or chronic disease; (2) the type of cells involved; myeloid (myeloid), lymphoid (lymphogenic), or monocytic; and (3) an increase or absence of an increase in the number of abnormal cells in a hematologic leukemia or non-leukemic disease (subleukemic). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, leukemia cutis, blast cell leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute leukemia, myeloblastic leukemia, myeloid leukemia, myelomonocytic leukemia, myelomonocytic leukemia, myelomonocytic leukemia, myeloblastic ...blastic leukemia, myelomonocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomonocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomonocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomonocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomonocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomonocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomonocytic leukemia, myelo

[0210] In some embodiments, the disease is melanoma. The term "melanoma" is used to refer to tumors of the melanocyte system derived from the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentigo melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma or superficial spreading melanoma.

[0211] In some embodiments, the immune-mediated disease is selected from resistance caused by transplantation of heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nerve, duodenum, small bowel, or pancreatic islet cells; graft-versus-host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.

[0212] In some embodiments, the disease is an autoimmune disease. As used herein, the term "autoimmune disease" refers to a disease or condition in which a subject's immune system has an abnormal immune response to a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acute disseminated cerebrospinal meningitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, disease), chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome syndrome), fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly Wegener's Granulomatosis), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitisencephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), systemic lupus erythematosus (SLE), Lyme disease, chronic Meniere's disease (CMD), disease), microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's), neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease, PANDAS (childhood streptococcal autoimmune neuropsychiatric disorder), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonnage-Turner syndrome syndrome), pars plana ciliitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyglandular syndromes type I, II, and III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynauds phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome syndrome), sperm and testicular autoimmunity, stiff-man syndrome, subacute bacterial endocarditis (SBE), Susac's syndromesyndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, or Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

[0213] In some embodiments, the disclosed compositions or compounds can be used for immunosenescence. Immunosenience can refer to reduced immune function, resulting in, for example, impaired immune responses, especially to cancer, vaccination, infectious pathogens. It is related to both the host's ability to respond to infection and the development of long-term immune memory (especially through vaccination). This immunodeficiency is ubiquitous and is found to vary in both long-lived and short-lived species according to their age relative to life expectancy rather than chronological time. It is considered to be the main contributing factor to the increased frequency of morbidity and mortality in the elderly. Immunosenience is not a random degenerative phenomenon, but it seems to repeat the evolutionary pattern in reverse, and most parameters affected by immunosenescence seem to be under genetic control. Due to the continuous challenge of being inevitably exposed to various antigens (such as viruses and bacteria), immunosenescence can sometimes also be envisioned. Immunosenience is a multifactorial disease that, for example, causes many pathologically significant health problems in the elderly population. Age-dependent biological changes, such as the depletion of hematopoietic stem cells, the increase of PD1+ lymphocytes, the decline in the total number of phagocytes and NK cells, and the decline in humoral immunity, contribute to the occurrence of immunosenescence. In one aspect, immunosenescence of an individual can be measured by measuring telomere length in immune cells (see, e.g., U.S. Pat. No. 5,741,677). Immunosenescence can also be determined by recording in an individual the number of naive CD4 and / or CD8 T cells, T cell pools, T cells expressing PD1 (e.g., PD-1 negative T cells below the normal number), or responses to vaccination in subjects aged greater than or equal to 65 years old. In certain embodiments, selective regulation of mTOR in certain T cell populations can improve vaccine efficacy in aging populations and enhance the effectiveness of cancer immunotherapy. The present disclosure provides a method for treating immunosenescence, comprising administering to a subject a therapeutically effective amount of one or more disclosed compositions or compounds.

[0214] In some embodiments, the disease is organ or tissue transplant rejection (e.g., heart, lung, liver, kidney, pancreas, skin or corneal transplant; graft-versus-host disease), restenosis, hamartoma syndrome (e.g., tuberous sclerosis or Cowden Disease), lymphangioleiomyomatosis, retinitis pigmentosa, encephalomyelitis, insulin-dependent diabetes mellitus, lupus, dermatomyositis, arthritis, rheumatic disease, steroid-resistant acute lymphoblastic leukemia, fibrosis, scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis, pulmonary hypertension, multiple sclerosis, VHL syndrome, Carney complex, familial adenonamtous polyposis, juvenile polyposis syndrome, BHD syndrome (Birt-Hogg-Duke syndrome), familial hypertrophic cardiomyopathy, WPW syndrome (Wolf-Parkinson-White syndrome), syndrome), Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia caused by tau mutations, spinocerebellar ataxia type 3, motor neuron disease caused by SOD1 mutations, neuronal ceroid lipofuscinosis / Batten disease (pediatric neurodegeneration), wet macular degeneration, dry macular degeneration, muscle wasting (atrophy, cachexia), muscle diseases (e.g., Danon's disease), bacterial infections, viral infections, Mycobacterium tuberculosis, group A Streptococcus, HSV type 1, HIV infection, neurofibromatosis (e.g., neurofibromatosis type 1), or Peutz-Jeghers syndrome.

[0215] In some embodiments, the disease is a neurodegenerative disease.As used herein, the term "neurodegenerative disease" refers to a disease or disorder in which the function of a subject's nervous system is impaired. Examples of neurodegenerative diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, dementia with Lewy bodies, Machado-Joseph disease, disease) (type 3 spinocerebellar ataxia), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0216] In some embodiments, the disease is a metabolic disease. As used herein, the term "metabolic disease" refers to such a disease or condition, wherein the metabolism or metabolic system (e.g., the function of storing or utilizing energy) of the subject becomes impaired. Examples of metabolic diseases that can be treated with compounds, pharmaceutical compositions or methods as described herein include diabetes (e.g., type I or type II), obesity, metabolic syndrome or mitochondrial disease (e.g., mitochondrial dysfunction or mitochondrial dysfunction).

[0217] In some embodiments, the disease is an inflammatory disease. As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (eg, increased levels of inflammation compared to a control, such as a healthy person without the disease). Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0218] In some embodiments, the disease is a cardiovascular disease.As used herein, the term "cardiovascular disease" refers to a disease or condition in which the function of a subject's cardiovascular system becomes impaired. Examples of cardiovascular diseases that can be treated with the compounds, pharmaceutical compositions or methods described herein include congestive heart failure; arrhythmogenic syndromes (e.g., paroxysmal tachycardia, delayed afterdepolarization, ventricular tachycardia, sudden tachycardia, exercise-induced arrhythmia, long QT syndrome, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or intracardiac thromboembolic disorders); atherosclerosis; restenosis; peripheral arterial disease; coronary artery bypass grafting; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent) the following are intended to describe any of the following: acute myocardial infarction (AMI); myocardial infarction; non-Q wave myocardial infarction; non-STE myocardial infarction; coronary artery disease; ischemic heart disease; myocardial ischemia; ischemia; sudden ischemic death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary thrombosis; cerebral artery thrombosis, cerebral embolism; renal embolism; pulmonary embolism; thrombosis (e.g., associated with prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e.g., associated with atherosclerosis, surgery, prolonged immobilization, atrial fibrillation, congenital thrombophilia, cancer, diabetes, hormones, or pregnancy); or atrial arrhythmia (e.g., supraventricular arrhythmia, atrial arrhythmia, atrial flutter, or atrial fibrillation).

[0219] The present disclosure also provides methods for treating age-related conditions, comprising administering in a subject in need thereof. In certain embodiments, the age-related conditions are selected from sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, shortened life expectancy, impaired renal function, and age-related hearing loss, age-related mobility disability (e.g., frailty), cognitive decline, age-related dementia, memory impairment, tendon stiffness, cardiac dysfunction such as cardiac hypertrophy and systolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes.

[0220] In particular, various embodiments of the present disclosure relate to methods, uses and medicaments directed to treating the following cancers.

[0221] In some embodiments, the cancer is ampullary cancer, appendix cancer, bile duct cancer, bladder cancer, blood proliferative disorders, bone cancer, brain and neurovascular tumors, breast cancer, cancer of unknown primary origin, cervical cancer, colorectal cancer, endometrial cancer, esophageal and gastric cancer, gastrointestinal cancer, germ cell cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, neurogenic cancer, neuroendocrine tumors, eye cancer, ovarian cancer, ovarian endometriosis, pancreatic cancer, peritoneal cancer, penile cancer, prostate cancer, rhabdomyosarcoma, sarcoma, sex cord-stromal tumors, skin cancer, soft tissue cancer, testicular cancer, uterine cancer, and vulvar cancer. In some embodiments, the cancer is selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer, and rhabdomyosarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer.

[0222] In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma, salivary gland cancer, or thyroid cancer. In some embodiments, the thyroid cancer is thyroid adenocarcinoma. In some embodiments, the head and neck cancer is salivary gland cancer. As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 was unexpectedly effective for the treatment of salivary gland cancer, with 1 subject showing a 63% reduction in tumor size.

[0223] In some embodiments, cancer is a blood cancer. In some embodiments, blood cancer is leukemia, lymphoma, myeloproliferative disease, multiple myeloma or myelodysplastic syndrome. In some embodiments, leukemia is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) or chronic myeloid leukemia (CML). In some embodiments, lymphoma is mantle cell lymphoma (MCL), B-acute lymphoblastic lymphoma, non-Hodgkin lymphoma (e.g., Burkitt's lymphoma, small cell lymphoma and large cell lymphoma) or Hodgkin lymphoma.

[0224] In some embodiments, the cancer is gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is GI neuroendocrine cancer, gastrointestinal stromal tumor, gastric cancer, anal cancer, rectal cancer, colorectal cancer (CRC), intestinal cancer, or small intestine cancer. In some embodiments, the gastrointestinal cancer is colorectal cancer.

[0225] In some embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma (RCC).

[0226] In some embodiments, the cancer is liver cancer. In some embodiments, the liver cancer is hepatobiliary carcinoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, or hemangioma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the liver cancer is hepatoblastoma.

[0227] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer.

[0228] In some embodiments, the cancer is ovarian cancer.

[0229] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor (PNET).

[0230] In some embodiments, the cancer is prostate cancer.

[0231] In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is melanoma. In some embodiments, the skin cancer is basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, or psoriasis.

[0232] In some embodiments, the cancer is uterine cancer.

[0233] In some embodiments, the cancer is a sarcoma.The term "sarcoma" generally refers to a tumor composed of a material like embryonic connective tissue and is typically composed of tightly packed cells embedded in a fibrillar or homogeneous mass. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms tumor, sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, sarcoma), angiosarcoma, leukemic sarcoma, malignant stromal tumor sarcoma, extraperiosteal sarcoma, reticular cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0234] In some embodiments, the cancer is a carcinoma.The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, alveolar carcinoma, adenoid carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus carcinoma, cribriform carcinoma, armor carcinoma, cutaneous carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, carcinoma durum, germinal carcinoma, encephaloid carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, gelatinous carcinoma, fibrocar ... carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granular cell carcinoma, hair-matrix carcinoma, hematogenous carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyalinoid carcinoma, adrenal carcinoma, immature germ cell carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma (carcinoma lenticulare), lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, carcinoma muciparum, mucous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthocyte carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinomacarcinoma, carcinoma scroti, signet ring cell carcinoma, carcinoma simplex, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous cell carcinoma, squamous cell carcinoma, stringcarcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0235] In some embodiments, the cancer is a solid tumor.

[0236] In some embodiments, the cancer is characterized by a genotypic aberration that activates the mammalian target of rapamycin (mTOR) pathway. In some embodiments, the cancer comprises a mutation in the mTOR pathway.

[0237] In some embodiments, the genotypic aberration or mutation is a genotypic aberration or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1, or TSC2, or a combination thereof.

[0238] In some embodiments, the genotype aberration or mutation is a genotype aberration or mutation of PTEN. In some embodiments, the PTEN mutation is a dominant negative mutation. As described herein, the dosage of the dual-site mTOR inhibitor RMC-5552 is effective for treating cancers with PTEN mutations, wherein 1 subject showed a partial remission (PR) and 2 subjects showed a response of stable disease (SD).

[0239] In some embodiments, the genotypic aberration is a mutation of PIK3CA. As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 was effective for treating cancers with a mutation of PIK3CA, with 3 subjects exhibiting a response of stable disease (SD).

[0240] In some embodiments, the genotypic aberration is a mutation of TSC2. As described herein, doses of the dual-site mTOR inhibitor RMC-5552 were effective for treating cancers comprising a mutation of TSC2, with 2 subjects exhibiting a response of stable disease (SD).

[0241] In some embodiments, the cancer comprises KRAS G12C In some embodiments, the cancer comprises a co-occurring KRAS mutation. G12CAs described herein, the dose of the dual-site mTOR inhibitor RMC-5552 is effective for treating patients with STK11 mutations and KRAS G12C In some embodiments, the cancer contains a co-occurring KRAS G12C and PIK3CA E545K mutation.

[0242] In some embodiments, the cancer is characterized by increased mTORC1 activity. In some embodiments, the cancer is characterized by decreased 4EBP1 activity.

[0243] In some embodiments, the cancer comprises a mutation of the Myc family. In some embodiments, the cancer comprises an amplification of MYC, MYCL, MYCN, or a combination thereof and / or a dependency on MYC, MYCL, MYCN, or a combination thereof. In some embodiments, the cancer comprises an amplification of MYC. As described herein, the dosage of the dual-site mTOR inhibitor RMC-5552 is effective for treating cancers with an amplification of MYC, wherein 1 subject exhibits a response of stable disease (SD).

[0244] In some embodiments, the cancer comprises a mutation in NFE2L2 (also known as NRF2). As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 is effective for treating cancers comprising a mutation in NFE2L2, with 1 subject demonstrating a response of stable disease (SD).

[0245] In some embodiments, the cancer comprises a BRAF fusion. As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 was effective for treating cancer comprising a BRAF fusion, with 1 subject demonstrating a response of stable disease (SD).

[0246] In some embodiments, the cancer is colorectal cancer and comprises a mutation of PIK3CA. In some embodiments, the cancer is colorectal cancer and comprises an amplification of MYC. In some embodiments, the cancer is colorectal cancer and comprises a mutation of PIK3CA and an amplification of MYC. As described herein, the dosage of the dual-site mTOR inhibitor RMC-5552 is effective for treating colorectal cancer comprising a mutation of PIK3CA and an amplification of MYC, wherein 1 subject exhibits a response of stable disease (SD).

[0247] In some embodiments, cancer is head and neck cancer and comprises a mutation of PIK3CA. As described herein, the dosage of the dual-site mTOR inhibitor RMC-5552 is effective for treating a head and neck cancer comprising a mutation of PIK3CA, wherein one subject exhibits a response of stable disease (SD). In some embodiments, cancer is head and neck cancer and comprises a mutation of PTEN. As described herein, the dosage of the dual-site mTOR inhibitor RMC-5552 is effective for treating a head and neck cancer comprising a mutation of PTEN, wherein one subject exhibits a partial remission (PR). In some embodiments, cancer is head and neck cancer and comprises a mutation of PIK3CA and a mutation of PTEN.

[0248] In some embodiments, the cancer is liver cancer and comprises a mutation in NFE2L2. In some embodiments, the cancer is hepatocellular carcinoma and comprises a mutation in NFE2L2. As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 is effective for treating hepatocellular carcinoma comprising a mutation in NFE2L2, with 1 subject demonstrating a response of stable disease (SD).

[0249] In some embodiments, the cancer is ovarian cancer and comprises a mutation in TSC2. As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 was effective for treating ovarian cancer comprising a mutation in TSC2, with 1 subject demonstrating a response of stable disease (SD).

[0250] In some embodiments, the cancer is pancreatic cancer and comprises a mutation in STK11. In some embodiments, the cancer is pancreatic cancer and comprises a mutation in KRAS G12C In some embodiments, the cancer is pancreatic cancer and comprises a mutation in STK11 and KRAS G12C As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 is effective for the treatment of malignant tumors containing mutations of STK11 and KRAS G12C The mutated pancreatic cancer was effective, with 1 subject demonstrating a stable disease (SD) response.

[0251] In some embodiments, the cancer is prostate cancer and comprises a mutation in PTEN. As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 is effective for treating prostate cancer comprising a mutation in PTEN, with 1 subject demonstrating a response of stable disease (SD).

[0252] In some embodiments, cancer is uterine cancer and comprises a mutation of PIK3CA. In some embodiments, cancer is uterine cancer and comprises a mutation of PTEN. In some embodiments, cancer is uterine cancer and comprises a mutation of PIK3CA and a mutation of PTEN. In some embodiments, cancer is uterine cancer and comprises a mutation of TSC2. In some embodiments, cancer is uterine cancer and comprises a mutation of PIK3CA and a mutation of TSC2. In some embodiments, cancer is uterine cancer and comprises a mutation of PIK3CA, a mutation of PTEN and a mutation of TSC2. As described herein, the dosage of the dual-site mTOR inhibitor RMC-5552 is effective for treating uterine cancer comprising a mutation of PIK3CA, a mutation of PTEN and a mutation of TSC2, wherein 1 subject exhibits a stable disease (SD) response.

[0253] In some embodiments, the cancer is lung cancer and comprises a BRAF fusion. As described herein, the dose of the dual-site mTOR inhibitor RMC-5552 was effective for treating lung cancer comprising a BRAF fusion, with 1 subject demonstrating a response of stable disease (SD).

[0254] In some embodiments, the cancer comprises a RAS mutation. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, gastrointestinal neuroendocrine cancer, ovarian cancer, sex cord-stromal tumor cancer, hepatobiliary cancer, or bladder cancer.

[0255] In some embodiments, the cancer comprises greater than about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, greater than about 99% clonality of pathogenic variants in PIK3CA, PTEN, TSC1, or TSC2. In some embodiments, the cancer comprises greater than about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, greater than about 99% clonality of pathogenic variants in PTEN. In some embodiments, the cancer comprises greater than about 90% clonality of pathogenic variants in PTEN. In some embodiments, the cancer comprises greater than about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, greater than about 99% clonality of pathogenic variants in TSC1. In some embodiments, the cancer comprises greater than about 90% clonality of pathogenic variants in TSC1. In some embodiments, the cancer comprises greater than about 90% clonality of pathogenic variants in PTEN. In some embodiments, the cancer comprises greater than about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, greater than about 99% clonality of pathogenic variants in TSC2. In some embodiments, the cancer comprises greater than about 90% clonality of pathogenic variants in TSC2. In some embodiments, the cancer comprises greater than about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, greater than about 99% clonality of pathogenic variants in PIK3CA. In some embodiments, the cancer comprises greater than about 90% clonality of pathogenic variants in PIK3CA.

[0256] In some embodiments, the methods result in tumor regression. In some embodiments, the methods result in tumor cell apoptosis. Preventing or treating acquired resistance to RAS inhibitors

[0257] In some embodiments, the method comprises administering a RAS inhibitor (e.g., KRAS G12C inhibitor) in combination with an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) to delay, prevent, or treat response to a RAS inhibitor (e.g., KRAS G12C In some embodiments, the disclosure includes methods for inducing the expression of RAS in cells by combining cells with a RAS inhibitor (e.g., a KRAS(OFF) inhibitor, such as a KRASG12C In some embodiments, the present disclosure includes methods for inducing apoptosis in cells (e.g., tumor cells) by contacting cells with a combination of a RAS inhibitor (e.g., a RAS(ON) inhibitor, such as KRAS G12C A method of inducing apoptosis in a cell (e.g., a tumor cell) by contacting a combination of an mTOR (ON) inhibitor) with an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552).

[0258] As used herein, the term "preventing acquired resistance" means avoiding the development of acquired or adaptive resistance. Thus, for example, in preventing the development of resistance to KRAS G12C The use of mTOR inhibitors described herein (e.g., dual-site mTOR inhibitors, e.g., RMC-5552) in acquired / adaptive resistance to inhibitors means that G12C any detectable resistance to the inhibitor exists prior to administration of the mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552), and no resistance to KRAS occurs as a result of administration of such an mTOR inhibitor (e.g., a dual-site mTOR inhibitor, e.g., RMC-5552) G12C Inhibitor resistance.

[0259] The present disclosure provides methods for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject about 3 mg / week to about 25 mg / week of a dual-site mTOR inhibitor, wherein the subject has received or will receive administration of the RAS inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0260] The present disclosure provides a method for treating acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject about 3 mg / week to about 25 mg / week of a dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0261] In some embodiments, the method of delaying, preventing or treating acquired resistance to RAS inhibitors comprises administering to a subject an effective amount of a RAS inhibitor. RAS inhibitors are described in more detail in the Combination section of the present disclosure, and all such RAS inhibitors are contemplated for use in methods of delaying, preventing or treating acquired resistance to RAS inhibitors.

[0262] In some embodiments, the RAS inhibitor targets a specific RAS mutation. In some embodiments, the RAS inhibitor targets a KRAS mutation. In some embodiments, the RAS inhibitor targets a KRAS mutation. G12C mutation.

[0263] In some embodiments, the RAS inhibitor is a KRAS (OFF) inhibitor. In some embodiments, the KRAS (OFF) inhibitor is AMG 510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255 or a pharmaceutically acceptable salt of any of the foregoing.

[0264] In some embodiments, the RAS inhibitor is a RAS(ON) inhibitor. In some embodiments, the RAS(ON) inhibitor is a KRAS(ON) inhibitor. In some embodiments, the KRAS(ON) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, RMC-0708, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the KRAS(ON) inhibitor is a KRAS G12C In some embodiments, KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, a RAS inhibitor is administered to a subject to treat or prevent cancer. In some embodiments, the cancer comprises KRAS G12C In some embodiments, the cancer comprises a co-occurring KRAS mutation. G12C and STK11 mutations. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, the cancer comprises a co-occurring KRAS G12C and PIK3CA E545K Mutation. In some embodiments, the cancer is colorectal cancer.

[0266] In some embodiments, the methods result in tumor regression. In some embodiments, the methods result in tumor cell apoptosis. Exemplary embodiments

[0267] Embodiment I-1. A method of treating a subject having cancer, the method comprising administering to the subject a dual-site mTOR inhibitor at a dose of about 3 mg / week to about 25 mg / week; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0268] Embodiment I-2. A method of treating a subject having salivary gland cancer, the method comprising administering to the subject a dual-site mTOR inhibitor at a dose of about 3 mg / week to about 25 mg / week; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0269] Embodiment I-3. A method according to embodiment I-1 or I-2, wherein the dosage is about 4 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week, or about 7 mg / week to about 8 mg / week.

[0270] Embodiment I-4. A method according to any one of embodiments I-1 to I-3, wherein the dosage is about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, or about 10 mg / week.

[0271] Embodiment I-5. The method according to any one of Embodiments I-1 to I-4, wherein the dose is administered via intravenous infusion.

[0272] Embodiment I-6. The method of embodiment I-5, wherein the dose is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours.

[0273] Embodiment I-7. The method of embodiment I-5 or I-6, wherein the dose is administered over about 1 hour.

[0274] Embodiment I-8. The method of any one of Embodiments I-1 to I-7, wherein the cancer is characterized by a genotypic aberration that activates the mammalian target of rapamycin (mTOR) pathway.

[0275] Embodiment I-9. A method according to any one of Embodiments I-1 to I-8, wherein the cancer comprises a mutation in the mTOR pathway.

[0276] Embodiment I-10. A method according to embodiment I-8 or I-9, wherein the genotype aberration or the mutation is a genotype aberration or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1 or TSC2 or a combination thereof.

[0277] Embodiment I-11. The method according to any one of Embodiments I-8 to I-10, wherein the genotypic aberration or the mutation is a genotypic aberration or mutation of PTEN.

[0278] Embodiment I-12. The method of embodiment I-10 or I-11, wherein the PTEN mutation is a dominant negative mutation.

[0279] Embodiment I-13. The method of any one of Embodiments I-1 to I-12, wherein the cancer is characterized by increased mTORC1 activity.

[0280] Embodiment I-14. The method of any one of Embodiments I-1 to I-13, wherein the cancer is characterized by decreased 4EBP1 activity.

[0281] Embodiment I-15. A method according to any one of Embodiments I-1 to I-14, wherein the cancer comprises a mutation in the Myc family.

[0282] Embodiment I-16. A method according to embodiment I-15, wherein the cancer comprises amplification of MYC, MYCL, MYCN or a combination thereof and / or dependence on MYC, MYCL, MYCN or a combination thereof.

[0283] Embodiment I-17. A method according to any one of Embodiments I-1 to I-16, wherein the cancer comprises a mutation in NFE2L2.

[0284] Embodiment I-18. A method according to any one of Embodiments I-1 to I-17, wherein the cancer comprises a BRAF fusion.

[0285] Embodiment I-19. A method according to any one of embodiments I-1 or I-3 to I-18, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer and rhabdomyosarcoma.

[0286] Embodiment I-20. A method according to any one of Embodiments I-1 or I-3 to I-19, wherein the cancer is a solid tumor.

[0287] Embodiment I-21. A method according to any one of Embodiments I-1 or I-3 to I-20, wherein the cancer is head and neck cancer.

[0288] Embodiment 1-22. The method of embodiment 1-21, wherein the cancer is salivary gland cancer.

[0289] Embodiment I-23. A method according to any one of Embodiments I-1 to I-22, wherein the subject is a human.

[0290] Embodiment 1-24. The method of any one of Embodiments 1-1 to 1-23, wherein the method further comprises administering a dexamethasone mouthwash to the subject.

[0291] Embodiment 1-25. The method of embodiment 1-24, wherein the dexamethasone mouthwash comprises about 0.5 mg / 5 mL dexamethasone.

[0292] Embodiment 1-26. The method of embodiment 1-24 or 1-25, wherein about 2.5 mL of the dexamethasone mouthwash is administered to the subject.

[0293] Embodiment 1-27. The method of any one of embodiments 1-24 to 1-26, wherein the dexamethasone mouthwash is administered 1, 2, 3, or 4 times daily.

[0294] Embodiment 1-28. The method of any one of Embodiments 1-1 to 1-27, wherein the method further comprises administering a tacrolimus mouthwash to the subject.

[0295] Embodiment 1-29. The method of embodiment 1-28, wherein the tacrolimus mouthwash comprises about 0.5 mg / mL tacrolimus.

[0296] Embodiment 1-30. The method of embodiment 1-28 or 1-29, wherein about 2.5 mL of the tacrolimus mouthwash is administered to the subject.

[0297] Embodiment 1-31. The method of any one of embodiments 1-28 to 1-30, wherein the tacrolimus mouthwash is administered 1, 2, 3 or 4 times daily.

[0298] Embodiment 1-32. The method of any one of Embodiments 1-28 to 1-31, wherein the tacrolimus mouthwash is administered on the day of or immediately prior to administration of the dual-site mTOR inhibitor.

[0299] Embodiment 1-33. The method of any one of Embodiments 1-1 to 1-23, wherein the method further comprises administering to the subject a combination mouthwash, wherein the combination mouthwash comprises dexamethasone and tacrolimus.

[0300] Embodiment 1-34. The method of embodiment 1-33, wherein the combination mouthwash comprises about 0.5 mg / 5 mL dexamethasone.

[0301] Embodiment 1-35. The method of embodiment 1-33 or 1-34, wherein the combination mouthwash comprises about 0.5 mg / mL tacrolimus.

[0302] Embodiment 1-36. The method of any one of Embodiments 1-33 to 1-35, wherein about 2.5 mL of the combination mouthwash is administered to the subject.

[0303] Embodiment 1-37. The method of any one of embodiments 1-33 to 1-36, wherein the combination mouthwash is applied 1, 2, 3 or 4 times daily.

[0304] Embodiment 1-38. The method of any one of Embodiments 1-33 to 1-37, wherein the combination mouthwash is administered on the day of or immediately prior to administration of the dual-site mTOR inhibitor.

[0305] Embodiment 1-39. The method of any one of Embodiments 1-1 to 1-38, wherein the method further comprises applying ice to the oral cavity of the subject.

[0306] Embodiment I-40. The method of Embodiment I-39, wherein the ice is applied for about 10 minutes before administration of the dual-site mTOR inhibitor, during administration of the dual-site mTOR inhibitor, and after administration of the dual-site mTOR inhibitor.

[0307] Embodiment 1-41. The method of any one of Embodiments 1-24 to 1-40, wherein the dose is about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, or about 9 mg / week.

[0308] Embodiment 1-42. The method of any one of Embodiments 1-1 to 1-41, wherein the method further comprises administering a RAS inhibitor to the subject.

[0309] Embodiment 1-43. A method according to embodiment 1-42, wherein the RAS inhibitor targets a specific RAS mutation.

[0310] Embodiment I-44. The method of embodiment I-42 or I-43, wherein the RAS inhibitor targets a KRAS mutation.

[0311] Embodiment 1-45. A method according to any one of embodiments 1-42 to 1-44, wherein the RAS inhibitor targets KRAS G12C mutation.

[0312] Embodiment 1-46. The method of any one of Embodiments 1-42 to 1-45, wherein the RAS inhibitor is a KRAS(OFF) inhibitor.

[0313] Embodiment I-47. A method according to embodiment I-46, wherein the KRAS (OFF) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255 or a pharmaceutically acceptable salt of any one of the foregoing.

[0314] Embodiment 1-48. The method of any one of Embodiments 1-42 to 1-45, wherein the RAS inhibitor is a RAS(ON) inhibitor.

[0315] Embodiment 1-49. The method of embodiment 1-48, wherein the RAS(ON) inhibitor is a KRAS(ON) inhibitor.

[0316] Embodiment I-50. The method according to Embodiment I-49, wherein the KRAS(ON) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any one of the foregoing.

[0317] Embodiment I-51. A method according to embodiment I-49 or I-50, wherein the KRAS(ON) inhibitor is KRAS G12C (ON) inhibitor.

[0318] Embodiment I-52. A method according to embodiment I-51, wherein the KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0319] Embodiment 1-53. A method according to any one of Embodiments 1-1 to 1-52, wherein the cancer comprises KRAS G12C mutation.

[0320] Embodiment 1-54. A method according to any one of Embodiments 1-1 to 1-53, wherein the cancer comprises a co-occurring KRAS G12C and STK11 mutations.

[0321] Embodiment 1-55. A method according to any one of Embodiments 1-1 to 1-54, wherein the cancer comprises a co-occurring KRAS G12C and PIK3CA E545K mutation.

[0322] Embodiment I-56. A method according to any one of Embodiments I-1 to I-20 and I-23 to I-55, wherein the cancer is colorectal cancer and comprises a mutation of PIK3CA, an amplification of MYC, or a mutation of PIK3CA and an amplification of MYC.

[0323] Embodiment I-57. A method according to any one of Embodiments I-1 to I-21 and I-23 to I-55, wherein the cancer is head and neck cancer and comprises a mutation in PIK3CA, a mutation in PTEN, or a mutation in PIK3CA and a mutation in PTEN.

[0324] Embodiment 1-58. A method according to any one of Embodiments 1-1 to 1-20 and 1-23 to 1-55, wherein the cancer is hepatocellular carcinoma and comprises a mutation in NFE2L2.

[0325] Embodiment 1-59. A method according to any one of Embodiments 1-1 to 1-20 and 1-23 to 1-55, wherein the cancer is ovarian cancer and comprises a mutation in TSC2.

[0326] Embodiment 1-60. A method according to any one of Embodiments 1-1 to 1-20 and 1-23 to 1-55, wherein the cancer is pancreatic cancer and comprises a mutation in STK11, KRASG12C Mutation or mutation of STK11 and KRAS G12C mutation.

[0327] Embodiment I-61. A method according to any one of Embodiments I-1 to I-20 and I-23 to I-55, wherein the cancer is prostate cancer and comprises a mutation in PTEN.

[0328] Embodiment I-62. A method according to any one of Embodiments I-1 to I-20 and I-23 to I-55, wherein the cancer is uterine cancer and comprises a mutation of PIK3CA, a mutation of PIK3CA, a mutation of TSC2, or a combination thereof.

[0329] Embodiment 1-63. A method according to any one of Embodiments 1-1 to 1-20 and 1-23 to 1-55, wherein the cancer is lung cancer and comprises a BRAF fusion.

[0330] Embodiment 1-64. The method of any one of Embodiments 1-1 to 1-63, wherein the method results in tumor regression.

[0331] Embodiment 1-65. A method according to any one of Embodiments 1-1 to 1-64, wherein the method results in apoptosis of tumor cells.

[0332] Embodiment 1-66. A method for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject about 3 mg / week to about 25 mg / week of a dual-site mTOR inhibitor, wherein the subject has received or will receive administration of the RAS inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0333] Embodiment 1-67. A method of treating acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject about 3 mg / week to about 25 mg / week of a dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0334] Embodiment 1-68. The method of embodiment 1-66 or 1-67, further comprising administering to the subject an effective amount of the RAS inhibitor.

[0335] Embodiment 1-69. A method according to embodiment 1-68, wherein the RAS inhibitor targets a specific RAS mutation.

[0336] Embodiment I-70. The method of any one of Embodiments I-66 to I-69, wherein the RAS inhibitor targets a KRAS mutation.

[0337] Embodiment I-71. A method according to any one of Embodiments I-66 to I-70, wherein the RAS inhibitor targets KRAS G12C mutation.

[0338] Embodiment I-72. The method of any one of Embodiments I-66 to I-71, wherein the RAS inhibitor is a KRAS(OFF) inhibitor.

[0339] Embodiment I-73. A method according to embodiment I-72, wherein the KRAS (OFF) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255 or a pharmaceutically acceptable salt of any one of the foregoing.

[0340] Embodiment I-74. The method of any one of Embodiments I-66 to I-71, wherein the RAS inhibitor is a RAS(ON) inhibitor.

[0341] Embodiment 1-75. The method of embodiment 1-74, wherein the RAS(ON) inhibitor is a KRAS(ON) inhibitor.

[0342] Embodiment 1-76. The method of embodiment 1-75, wherein the KRAS(ON) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any one of the foregoing.

[0343] Embodiment I-77. A method according to embodiment I-75 or I-76, wherein the KRAS(ON) inhibitor is KRAS G12C (ON) inhibitor.

[0344] Embodiment 1-78. A method according to embodiment 1-77, wherein the KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0345] Embodiment 1-79. The method of any one of Embodiments 1-66 to 1-78, wherein the RAS inhibitor is administered to the subject to treat or prevent cancer.

[0346] Embodiment 1-80. A method according to embodiment 1-79, wherein the cancer comprises KRAS G12C mutation.

[0347] Embodiment 1-81. A method according to embodiment 1-79 or 1-80, wherein the cancer comprises a co-occurring KRAS G12C and STK11 mutations.

[0348] Embodiment 1-82. A method according to any one of Embodiments 1-79 to 1-81, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer.

[0349] Embodiment 1-83. A method according to any one of Embodiments 1-79 to 1-82, wherein the cancer comprises a co-occurring KRAS G12C and PIK3CA E545K mutation.

[0350] Embodiment 1-84. A method according to any one of Embodiments 1-79 to 1-81 and 1-83, wherein the cancer is colorectal cancer.

[0351] Embodiment 1-85. The method of any one of Embodiments 1-66 to 1-84, wherein the method results in tumor regression.

[0352] Embodiment 1-86. A method according to any one of Embodiments 1-66 to 1-84, wherein the method results in apoptosis of tumor cells.

[0353] Embodiment 1-87. Use of a dual-site mTOR inhibitor in treating cancer, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0354] Embodiment 1-88. Use of a dual-site mTOR inhibitor in the manufacture of a medicament for treating cancer, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0355] Embodiment 1-89. A dual-site mTOR inhibitor for use in a method of treating cancer, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0356] Embodiment 1-90. An agent for treating cancer, the agent comprising a dual-site mTOR inhibitor, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor to a subject in need thereof; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0357] Embodiment I-91. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-87 to I-90, wherein the dosage is about 4 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week, or about 7 mg / week to about 8 mg / week.

[0358] Embodiment I-92. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-87 to I-91, wherein the dosage is about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, or about 10 mg / week.

[0359] Embodiment I-93. The use, the dual-site mTOR inhibitor for use, or the medicament for use in treatment according to any one of Embodiments I-87 to I-92, wherein the dose is administered via intravenous infusion.

[0360] Embodiment I-94. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to Embodiment I-93, wherein the dose is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours.

[0361] Embodiment I-95. The use, the dual-site mTOR inhibitor for use or the medicament for treatment according to Embodiment I-93 or I-94, wherein the dose is administered over about 1 hour.

[0362] Embodiment I-96. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-95, wherein the cancer is characterized by a genotypic aberration that activates the mammalian target of rapamycin (mTOR) pathway.

[0363] Embodiment I-97. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-87 to I-96, wherein the cancer comprises a mutation in the mTOR pathway.

[0364] Embodiment I-98. The use according to Embodiment I-96 or I-97, the dual-site mTOR inhibitor for use or the agent for treatment, wherein the genotype aberration or the mutation is a genotype aberration or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1 or TSC2 or a combination thereof.

[0365] Embodiment I-99. The use, the dual-site mTOR inhibitor for use, or the agent for treatment according to any one of Embodiments I-96 to I-98, wherein the genotypic aberration or the mutation is a genotypic aberration or mutation of PTEN.

[0366] Embodiment I-100. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to Embodiment I-96 or I-99, wherein the PTEN mutation is a dominant negative mutation.

[0367] Embodiment I-101. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-100, wherein the cancer is characterized by increased mTORC1 activity.

[0368] Embodiment I-102. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-101, wherein the cancer is characterized by reduced 4EBP1 activity.

[0369] Embodiment I-103. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-102, wherein the cancer comprises a mutation in the Myc family.

[0370] Embodiment I-104. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to Embodiment I-103, wherein the cancer comprises an amplification of MYC, MYCL, MYCN, or a combination thereof and / or a dependence on MYC, MYCL, MYCN, or a combination thereof.

[0371] Embodiment I-105. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-104, wherein the cancer comprises a mutation in NFE2L2.

[0372] Embodiment I-106. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-105, wherein the cancer comprises a BRAF fusion.

[0373] Embodiment I-107. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-87 to I-106, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer, and rhabdomyosarcoma.

[0374] Embodiment I-108. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-87 to I-107, wherein the cancer is a solid tumor.

[0375] Embodiment I-109. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-108, wherein the cancer is head and neck cancer.

[0376] Embodiment I-110. The use, the dual-site mTOR inhibitor for use or the medicament for use according to embodiment I-109, wherein the cancer is salivary gland cancer.

[0377] Embodiment I-111. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-87 to I-110, wherein the subject is a human.

[0378] Embodiment I-112. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-111, wherein the method or the treatment further comprises administering a dexamethasone mouthwash to the subject.

[0379] Embodiment I-113. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to embodiment I-112, wherein the dexamethasone mouthwash comprises about 0.5 mg / 5 mL dexamethasone.

[0380] Embodiment I-114. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to Embodiment I-112 or I-113, wherein about 2.5 mL of the dexamethasone mouthwash is administered to the subject.

[0381] Embodiment I-115. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-112 to I-114, wherein the dexamethasone mouthwash is administered 1, 2, 3 or 4 times daily.

[0382] Embodiment I-116. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-115, wherein the method or the treatment further comprises administering a tacrolimus mouthwash to the subject.

[0383] Embodiment I-117. The use, the dual-site mTOR inhibitor for use, or the medicament for use in treatment according to Embodiment I-116, wherein the tacrolimus mouthwash comprises about 0.5 mg / mL tacrolimus.

[0384] Embodiment I-118. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to Embodiment I-116 or I-117, wherein about 2.5 mL of the tacrolimus mouthwash is administered to the subject.

[0385] Embodiment I-119. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-116 to I-118, wherein the tacrolimus mouthwash is administered 1, 2, 3 or 4 times daily.

[0386] Embodiment I-120. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-116 to I-119, wherein the tacrolimus mouthwash is administered on the day of or immediately before administration of the dual-site mTOR inhibitor.

[0387] Embodiment I-121. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-111, wherein the method or the treatment further comprises administering a combination mouthwash to the subject, wherein the combination mouthwash comprises dexamethasone and tacrolimus.

[0388] Embodiment I-122. The use, the dual-site mTOR inhibitor for use, or the medicament for use in treatment according to Embodiment I-121, wherein the combination mouthwash comprises about 0.5 mg / 5 mL dexamethasone.

[0389] Embodiment I-123. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to Embodiment I-121 or I-122, wherein the combination mouthwash comprises about 0.5 mg / mL tacrolimus.

[0390] Embodiment I-124. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-121 to I-123, wherein about 2.5 mL of the combination mouthwash is administered to the subject.

[0391] Embodiment I-125. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-121 to I-124, wherein the combination mouthwash is administered 1, 2, 3 or 4 times daily.

[0392] Embodiment I-126. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-121 to I-125, wherein the combination mouthwash is administered on the day of or immediately before administration of the dual-site mTOR inhibitor.

[0393] Embodiment 1-127. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments 1-87 to 1-126, wherein the method or the treatment further comprises applying ice to the oral cavity of the subject.

[0394] Embodiment I-128. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to Embodiment I-127, wherein the ice is applied for about 10 minutes before, during, and after the administration of the dual-site mTOR inhibitor.

[0395] Embodiment I-129. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-112 to I-128, wherein the dose is about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, or about 9 mg / week.

[0396] Embodiment I-130. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-87 to I-129, wherein the method or the treatment further comprises administering a RAS inhibitor to the subject.

[0397] Embodiment I-131. The use, the dual-site mTOR inhibitor for use or the medicament for treatment according to embodiment I-130, wherein the RAS inhibitor targets a specific RAS mutation.

[0398] Embodiment I-132. The use, the dual-site mTOR inhibitor for use, or the medicament for use in treatment according to Embodiment I-130 or I-131, wherein the RAS inhibitor targets a KRAS mutation.

[0399] Embodiment I-133. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-130 to I-132, wherein the RAS inhibitor targets KRAS G12C mutation.

[0400] Embodiment I-134. The use, dual-site mTOR inhibitor for use, or medicament for use in treatment according to any one of Embodiments I-130 to I-133, wherein the RAS inhibitor is a KRAS(OFF) inhibitor.

[0401] Embodiment I-135. The use, dual-site mTOR inhibitor for use, or agent for treatment according to embodiment I-134, wherein the KRAS (OFF) inhibitor is AMG 510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any one of the foregoing.

[0402] Embodiment I-136. The use, dual-site mTOR inhibitor for use, or medicament for use in treatment according to any one of Embodiments I-130 to I-133, wherein the RAS inhibitor is a RAS(ON) inhibitor.

[0403] Embodiment I-137. The use, the dual-site mTOR inhibitor for use or the medicament for use in treatment according to Embodiment I-136, wherein the RAS(ON) inhibitor is a KRAS(ON) inhibitor.

[0404] Embodiment I-138. The use, dual-site mTOR inhibitor for use, or agent for treatment according to Embodiment I-137, wherein the KRAS(ON) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any one of the foregoing.

[0405] Embodiment I-139. The use, dual-site mTOR inhibitor for use or medicament for treatment according to Embodiment I-137 or I-138, wherein the KRAS(ON) inhibitor is KRAS G12C (ON) inhibitor.

[0406] Embodiment I-140. The use, dual-site mTOR inhibitor for use or medicament for treatment according to embodiment I-139, wherein the KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0407] Embodiment I-141. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-140, wherein the cancer comprises KRAS G12C mutation.

[0408] Embodiment I-142. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-141, wherein the cancer comprises a co-occurring KRAS G12C and STK11 mutations.

[0409] Embodiment I-143. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-142, wherein the cancer comprises a co-occurring KRAS G12C and PIK3CA E545K mutation.

[0410] Embodiment I-144. A method according to any one of Embodiments I-87 to I-108 and I-111 to I-143, wherein the cancer is colorectal cancer and comprises a mutation of PIK3CA, an amplification of MYC, or a mutation of PIK3CA and an amplification of MYC.

[0411] Embodiment I-145. A method according to any one of Embodiments I-87 to I-109 and I-111 to I-143, wherein the cancer is head and neck cancer and comprises a mutation in PIK3CA, a mutation in PTEN, or a mutation in PIK3CA and a mutation in PTEN.

[0412] Embodiment 1-146. A method according to any one of Embodiments 1-87 to 1-108 and 1-111 to 1-143, wherein the cancer is hepatocellular carcinoma and comprises a mutation in NFE2L2.

[0413] Embodiment 1-147. A method according to any one of Embodiments 1-87 to 1-108 and 1-111 to 1-143, wherein the cancer is ovarian cancer and comprises a mutation in TSC2.

[0414] Embodiment I-148. A method according to any one of Embodiments I-87 to I-108 and I-111 to I-143, wherein the cancer is pancreatic cancer and comprises a mutation in STK11, KRAS G12C Mutation or mutation of STK11 and KRAS G12C mutation.

[0415] Embodiment 1-149. A method according to any one of Embodiments 1-87 to 1-108 and 1-111 to 1-143, wherein the cancer is prostate cancer and comprises a mutation in PTEN.

[0416] Embodiment I-150. A method according to any one of Embodiments I-87 to I-108 and I-111 to I-143, wherein the cancer is uterine cancer and comprises a mutation of PIK3CA, a mutation of PIK3CA, a mutation of TSC2, or a combination thereof.

[0417] Embodiment 1-151. A method according to any one of Embodiments 1-87 to 1-108 and 1-111 to 1-143, wherein the cancer is lung cancer and comprises a BRAF fusion.

[0418] Embodiment I-152. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-87 to I-151, wherein the method or the treatment results in tumor regression.

[0419] Embodiment I-153. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-87 to I-152, wherein the method or the treatment results in apoptosis of tumor cells.

[0420] Embodiment 1-154. A dual-site mTOR inhibitor for use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to the subject a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor, wherein the subject has received or will receive administration of the RAS inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0421] Embodiment 1-155. A combination of a dual-site mTOR inhibitor and a RAS inhibitor for simultaneous, separate or sequential use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0422] Embodiment 1-156. Use of a dual-site mTOR inhibitor for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the treatment comprising administering to the subject about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor, wherein the subject has received or will receive administration of the RAS inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0423] Embodiment 1-157. Use of a dual-site mTOR inhibitor in the manufacture of a medicament for the treatment of delaying or preventing acquired resistance to a RAS inhibitor, wherein the treatment comprises administering the medicament to deliver a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor to a subject in need thereof, wherein the subject has received or will receive administration of the RAS inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0424] Embodiment 1-158. A dual-site mTOR inhibitor for use in a method of delaying or preventing acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor, wherein the subject has received or will receive administration of the RAS inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0425] Embodiment 1-159. An agent for use in the treatment of delayed or prevented acquired resistance to a RAS inhibitor, the agent comprising a dual-site mTOR inhibitor, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor to a subject in need thereof, wherein the subject has received or will receive administration of the RAS inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0426] Embodiment 1-160. Use of a dual-site mTOR inhibitor for treating acquired resistance to a RAS inhibitor, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0427] Embodiment 1-161. Use of a dual-site mTOR inhibitor in the manufacture of a medicament for treating acquired resistance to a RAS inhibitor, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0428] Embodiment 1-162. A dual-site mTOR inhibitor for use in a method of treating acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0429] Embodiment 1-163. An agent for treating acquired resistance to a RAS inhibitor, the agent comprising a dual-site mTOR inhibitor, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the dual-site mTOR inhibitor to a subject in need thereof; wherein the dual-site mTOR inhibitor is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0430] Embodiment I-164. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-154 to I-163, wherein the method or the treatment further comprises administering an effective amount of the RAS inhibitor to the subject.

[0431] Embodiment I-165. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-154 to I-164, wherein the RAS inhibitor targets a specific RAS mutation.

[0432] Embodiment I-166. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-154 to I-165, wherein the RAS inhibitor targets a KRAS mutation.

[0433] Embodiment I-167. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-154 to I-166, wherein the RAS inhibitor targets KRAS G12C mutation.

[0434] Embodiment I-168. The use, dual-site mTOR inhibitor for use, or medicament for use in treatment according to any one of Embodiments I-154 to I-167, wherein the RAS inhibitor is a KRAS(OFF) inhibitor.

[0435] Embodiment I-169. The use according to embodiment I-168, the dual-site mTOR inhibitor for use or the medicament for treatment, wherein the KRAS (OFF) inhibitor is AMG 510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255 or a pharmaceutically acceptable salt of any one of the foregoing.

[0436] Embodiment I-170. The use, dual-site mTOR inhibitor for use, or medicament for use in treatment according to any one of Embodiments I-154 to I-167, wherein the RAS inhibitor is a RAS(ON) inhibitor.

[0437] Embodiment I-171. The use, the dual-site mTOR inhibitor for use or the medicament for use in treatment according to Embodiment I-170, wherein the RAS(ON) inhibitor is a KRAS(ON) inhibitor.

[0438] Embodiment I-172. The use, dual-site mTOR inhibitor for use, or agent for treatment according to Embodiment I-171, wherein the KRAS(ON) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any one of the foregoing.

[0439] Embodiment I-173. The use, dual-site mTOR inhibitor for use or medicament for treatment according to Embodiment I-171 or I-172, wherein the KRAS(ON) inhibitor is KRAS G12C (ON) inhibitor.

[0440] Embodiment I-174. The use, dual-site mTOR inhibitor for use or medicament for treatment according to embodiment I-173, wherein the KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0441] Embodiment I-175. The use, the dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-154 to I-174, wherein the RAS inhibitor is administered to the subject to treat or prevent cancer.

[0442] Embodiment I-176. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-156 to I-175, wherein the subject has cancer.

[0443] Embodiment I-177. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-154, I-155, I-175, and I-176, wherein the cancer comprises KRAS G12C mutation.

[0444] Embodiment I-178. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-154, I-155, and I-175 to I-177, wherein the cancer comprises a co-occurring KRAS G12C and STK11 mutations.

[0445] Embodiment I-179. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-154, I-155, and I-175 to I-178, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer.

[0446] Embodiment I-180. The use, dual-site mTOR inhibitor for use, or medicament for treatment according to any one of Embodiments I-154, I-155, I-175 to I-179, wherein the cancer comprises a co-occurring KRAS G12C and PIK3CA E545K mutation.

[0447] Embodiment I-181. The use, dual-site mTOR inhibitor for use, or the medicament for treatment according to any one of Embodiments I-154, I-155, I-175 to I-178, and I-180, wherein the cancer is colorectal cancer.

[0448] Embodiment I-182. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-154 to I-181, wherein the method or the treatment results in tumor regression.

[0449] Embodiment I-183. The use, dual-site mTOR inhibitor for use, or agent for treatment according to any one of Embodiments I-154 to I-182, wherein the method or the treatment results in apoptosis of tumor cells.

[0450] Embodiment II-1. A method of treating a subject having cancer, the method comprising administering to the subject a compound at a dose of about 3 mg / week to about 25 mg / week; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0451] Embodiment II-2. Use of a compound in the treatment of cancer, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0452] Embodiment II-3. Use of a compound in the manufacture of a medicament for treating cancer, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0453] Embodiment II-4. A compound for use in a method of treating cancer, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0454] Embodiment II-5. A medicament for treating cancer, the medicament comprising a compound, wherein the treatment comprises administering the medicament to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0455] Embodiment II-6. A method of treating a subject having salivary gland cancer, the method comprising administering to the subject a compound at a dose of about 3 mg / week to about 25 mg / week; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0456] Embodiment II-7. A method for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject about 3 mg / week to about 25 mg / week of a compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0457] Embodiment II-8. A method of treating acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg / week to about 25 mg / week of a compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0458] Embodiment II-9. A compound for use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to the subject a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0459] Embodiment II-10. A combination of a compound and a RAS inhibitor for simultaneous, separate or sequential use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0460] Embodiment II-11. Use of a compound for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the treatment comprising administering to the subject from about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0461] Embodiment II-12. Use of a compound in the manufacture of a medicament for the treatment of delaying or preventing acquired resistance to a RAS inhibitor, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0462] Embodiment II-13. A compound for use in a method of delaying or preventing acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0463] Embodiment II-14. A medicament for use in the treatment of delayed or prevented acquired resistance to a RAS inhibitor, the medicament comprising a compound, wherein the treatment comprises administering the medicament to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0464] Embodiment II-15. Use of a compound for treating acquired resistance to a RAS inhibitor, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0465] Embodiment II-16. Use of a compound in the manufacture of a medicament for treating acquired resistance to a RAS inhibitor, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0466] Embodiment II-17. A compound for use in a method of treating acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0467] Embodiment II-18. An agent for treating acquired resistance to a RAS inhibitor, the agent comprising a compound, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0468] Embodiment II-19. A method of treating or preventing mucositis in a subject in need thereof who has been, is being, or is to be treated with an mTOR inhibitor, the method comprising administering to the subject a tacrolimus solution.

[0469] Embodiment II-20. Use of a tacrolimus solution in a method for treating or preventing mucositis, wherein the treatment comprises administering the tacrolimus solution to a subject who has been, is being, or is to be treated with an mTOR inhibitor.

[0470] Embodiment II-21. Use of a tacrolimus solution in the manufacture of a medicament for treating or preventing mucositis, wherein the treatment comprises administering the medicament to a subject who has been, is being, or is to be treated with an mTOR inhibitor.

[0471] Embodiment II-22. A tacrolimus solution for use in a method of treating or preventing mucositis, the method comprising administering the tacrolimus solution to a subject who has been, is being, or is to be treated with an mTOR inhibitor.

[0472] Embodiment II-23. An agent for treating or preventing mucositis, the agent comprising a tacrolimus solution, wherein the treatment comprises administering the agent to a subject who has been, is being, or is to be treated with an mTOR inhibitor.

[0473] Embodiment II-24. The method, use, tacrolimus solution and medicament according to embodiments II-19 to II-23, wherein the mucositis is stomatitis.

[0474] Embodiment II-25. The method, use, tacrolimus solution and medicament according to embodiments II-19 to II-24, wherein the mTOR inhibitor is everolimus, sirolimus and albumin-bound sirolimus or a combination of the foregoing.

[0475] Embodiment II-26. The method, use, tacrolimus solution and medicament according to Embodiments II-19 to II-24, wherein the mTOR inhibitor has the structure Compounds or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

[0476] Embodiment II-27. The method, use, tacrolimus solution and medicament according to embodiment II-26, wherein the subject is administered a dose of about 3 mg / week to about 25 mg / week of the compound or its stereoisomer, tautomer or oxirane isomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0477] Embodiment II-28. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-18 and II-27, wherein the dosage is about 4 mg / week to about 25 mg / week, about 4 mg / week to about 14 mg / week, about 4 mg / week to about 12 mg / week, about 5 mg / week to about 25 mg / week, about 5 mg / week to about 14 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 6 mg / week to about 25 mg / week. g / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week, about 7 mg / week to about 25 mg / week, about 7 mg / week to about 14 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 25 mg / week, about 8 mg / week to about 14 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week.

[0478] Embodiment II-29. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of Embodiments II-1 to II-18, II-27 and II-28, wherein the dosage is about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week.

[0479] Embodiment II-30. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-18 and II-27 to II-30, wherein the dose in the first 1, 2, 3, 4 or 5 weeks is higher than the dose in subsequent weeks.

[0480] Embodiment II-31. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiment II-30, wherein the dosage for the first 1, 2, 3, 4 or 5 weeks is about 6 mg / week to about 25 mg / week, about 6 mg / week to about 20 mg / week, about 6 mg / week to about 16 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 8 mg / week to about 15 mg / week, about 12 mg / week to about 16 mg / week, about 12 mg / week to about 15 ... About 25 mg / week, about 8 mg / week to about 20 mg / week, about 8 mg / week to about 16 mg / week, about 8 mg / week to about 14 mg / week, about 8 mg / week to about 12 mg / week, about 8 mg / week to about 10 mg / week, about 10 mg / week to about 25 mg / week, about 10 mg / week to about 20 mg / week, about 10 mg / week to about 16 mg / week, about 10 mg / week to about 14 mg / week or about 10 mg / week to about 12 mg / week.

[0481] Embodiment II-32. The methods, uses, compounds, agents, combinations and tacrolimus solutions according to embodiments II-30 or II-31, wherein the dosage for the first 1, 2, 3, 4 or 5 weeks is about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week.

[0482] Embodiment II-33. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-30 to II-32, wherein the dose in the first week is higher than the dose in subsequent weeks.

[0483] Embodiment II-34. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-30 to II-33, wherein no administration is performed 1, 2, 3, 4 or 5 weeks after the doses in the first 1, 2, 3, 4 or 5 weeks.

[0484] Embodiment II-35. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-30 to II-34, wherein the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks is about 3 mg / week to about 12 mg / week, about 3 mg / week to about 10 mg / week, about 3 mg / week to about 8 mg / week, about 3 mg / week to about 6 mg / week, about 4 mg / week to about 12 mg / week, about 4 mg / week to about 10 mg / week, about 4 mg / week to about 8 mg / week, about 4 mg / week to about 6 mg / week. g / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 8 mg / week, about 5 mg / week to about 6 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 6 mg / week to about 8 mg / week, about 6 mg / week to about 7 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 10 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week.

[0485] Embodiment II-36. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-30 to II-35, wherein the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks is about 3 mg / week, about 3.5 mg / week, about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week to about 10 mg / week.

[0486] Embodiment II-37. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-30 to II-36, wherein: The dosage for the first 1, 2, 3, 4 or 5 weeks is from about 6 mg / week to about 25 mg / week, from about 6 mg / week to about 20 mg / week, from about 6 mg / week to about 16 mg / week, from about 6 mg / week to about 14 mg / week, from about 6 mg / week to about 12 mg / week, from about 6 mg / week to about 10 mg / week, from about 8 mg / week to about 25 mg / week, from about 8 mg / week to about 20 mg / week, from about 8 mg / week to about 16 mg / week, from about 8 mg / week to about 14 mg / week, from about 8 mg / week to about 12 mg / week, from about 8 mg / week to about 10 mg / week, from about 10 mg / week to about 25 mg / week, from about 10 mg / week to about 20 mg / week, from about 10 mg / week to about 16 mg / week, from about 10 mg / week to about 14 mg / week, or from about 10 mg / week to about 12 mg / week; No administration for 0, 1, 2, 3, 4, or 5 weeks thereafter; Subsequent doses are about 3 mg / week to about 12 mg / week, about 3 mg / week to about 10 mg / week, about 3 mg / week to about 8 mg / week, about 3 mg / week to about 6 mg / week, about 4 mg / week to about 12 mg / week, about 4 mg / week to about 10 mg / week, about 4 mg / week to about 8 mg / week, about 4 mg / week to about 6 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week. / week to about 8 mg / week, about 5 mg / week to about 6 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 6 mg / week to about 8 mg / week, about 6 mg / week to about 7 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 10 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week.

[0487] Embodiment II-38. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-30 to II-37, wherein: The dosage for the first 1, 2, 3, 4 or 5 weeks is about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week; No administration for 0, 1, 2, 3, 4, or 5 weeks thereafter; Subsequent doses are about 3 mg / week, about 3.5 mg / week, about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, or about 10 mg / week.

[0488] Embodiment II-39. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-18 and II-27 to II-38, wherein the dose is administered via intravenous infusion.

[0489] Embodiment II-40. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiment II-39, wherein the dose is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours or over about 1 hour to about 1.5 hours.

[0490] Embodiment II-41. The method, use, compound, medicament, combination or tacrolimus solution according to embodiment II-38 or 40, wherein the dose is administered over about 1 hour.

[0491] Embodiment II-42. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-41, wherein the subject is a human.

[0492] Embodiment II-43. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-42, wherein the method further comprises administering a dexamethasone solution to the subject.

[0493] Embodiment II-44. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-43, wherein the dexamethasone solution comprises about 0.5 mg / 5 mL dexamethasone.

[0494] Embodiment II-45. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-43 or II-44, wherein about 2.5 mL of the dexamethasone solution is administered to the subject.

[0495] Embodiment II-46. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-43 to II-45, wherein the dexamethasone solution is administered 1, 2, 3 or 4 times daily.

[0496] Embodiment II-47. The methods, uses, compounds, agents and combinations according to embodiments II-1 to II-18 and II-28 to II-46, wherein the method further comprises administering a tacrolimus solution to the subject.

[0497] Embodiment II-48. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-19 to II-27 and II-47, wherein the tacrolimus solution comprises about 0.1 mg / mL tacrolimus.

[0498] Embodiment II-49. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-19 to II-27, II-47 and II-48, wherein the tacrolimus solution comprises about 0.1 mg / mL tacrolimus.

[0499] Embodiment II-50. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-19 to II-27 and II-47 to II-49, wherein about 2.5 mL of the tacrolimus solution is administered to the subject.

[0500] Embodiment II-51. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-19 to II-27 and II-47 to II-50, wherein the tacrolimus solution is administered 1, 2, 3 or 4 times daily.

[0501] Embodiment II-52. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-19 to II-27 and II-47 to II-51, wherein the tacrolimus solution is administered on the day of administration of the dose or immediately before administration of the dose.

[0502] Embodiment II-53. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-52, wherein the method further comprises administering a combined solution to the subject, wherein the combined solution comprises dexamethasone and tacrolimus.

[0503] Embodiment II-54. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-53, wherein the combined solution comprises about 0.5 mg / 5 mL dexamethasone.

[0504] Embodiment II-55. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-53 or II-54, wherein the combined solution comprises about 0.5 mg / mL tacrolimus.

[0505] Embodiment II-56. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-53 to II-55, wherein about 2.5 mL of the combined solution is administered to the subject.

[0506] Embodiment II-57. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-53 to II-56, wherein the combined solution is administered 1, 2, 3 or 4 times daily.

[0507] Embodiment II-58. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-53 to II-57, wherein the combined solution is administered on the day of administration of the dose or immediately before administration of the dose.

[0508] Embodiment II-59. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-1 to II-58, wherein the method further comprises applying ice to the oral cavity of the subject.

[0509] Embodiment II-60. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiment II-59, wherein the ice is applied for about 10 minutes before administering the dose, during administering the dose, and after administering the dose.

[0510] Embodiment II-61. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-27 and II-43 to II-60, wherein the dosage is about 6 mg / week to about 25 mg / week, about 6 mg / week to about 20 mg / week, about 6 mg / week to about 16 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week or about 7 mg / week to about 8 mg / week.

[0511] Embodiment II-62. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-27 and II-43 to II-61, wherein the dosage is about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week.

[0512] Embodiment II-63. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-62, wherein the method further comprises administering a RAS inhibitor to the subject.

[0513] Embodiment II-64. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-63, further comprising administering an effective amount of the RAS inhibitor to the subject.

[0514] Embodiment II-65. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-63 or II-64, wherein the RAS inhibitor targets a specific RAS mutation.

[0515] Embodiment II-66. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-63 to II-65, wherein the RAS inhibitor targets a KRAS mutation.

[0516] Embodiment II-67. The method, use, compound, medicament, combination and tacrolimus solution according to Embodiment II-65 or II-66, wherein the RAS inhibitor targets KRAS G12C mutation.

[0517] Embodiment II-68. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-63 to II-67, wherein the RAS inhibitor is a KRAS(OFF) inhibitor.

[0518] Embodiment II-69. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-68, wherein the KRAS (OFF) inhibitor is AMG 510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255 or a pharmaceutically acceptable salt of any one of the foregoing.

[0519] Embodiment II-70. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-63 to II-67, wherein the RAS inhibitor is a RAS(ON) inhibitor.

[0520] Embodiment II-71. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-70, wherein the RAS(ON) inhibitor is a KRAS(ON) inhibitor.

[0521] Embodiment II-72. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-71, wherein the KRAS(ON) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839 or a pharmaceutically acceptable salt of any one of the foregoing.

[0522] Embodiment II-73. The method, use, compound, medicament, combination and tacrolimus solution according to Embodiment II-71 or II-75, wherein the KRAS(ON) inhibitor is KRAS G12C (ON) inhibitor.

[0523] Embodiment II-74. The method, use, compound, medicament, combination and tacrolimus solution according to Embodiment II-75 or II-73, wherein the KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0524] Embodiment II-75. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-7, II-8 and II-11 to II-74, wherein the subject has cancer.

[0525] Embodiment II-76. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiments II-1 to II-6, II-9, II-10 and II-75, wherein the cancer is characterized by a genotypic aberration that activates the mammalian target of rapamycin (mTOR) pathway.

[0526] Embodiment II-77. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiments II-1 to II-6, II-9, II-10, II-75 and II-76, wherein the cancer comprises a mutation in the mTOR pathway.

[0527] Embodiment II-78. The method, use, compound, agent, combination and tacrolimus solution according to embodiment II-75 or II-77, wherein the genotype aberration or the mutation is a genotype aberration or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1 or TSC2 or a combination thereof.

[0528] Embodiment II-79. The method, use, compound, medicament, combination and tacrolimus solution according to embodiments II-75 to II-78, wherein the genotypic aberration or the mutation is a genotypic aberration or mutation of PTEN.

[0529] Embodiment II-80. The method, use, compound, medicament, combination and tacrolimus solution according to embodiment II-79, wherein the PTEN mutation is a dominant negative mutation.

[0530] Embodiment II-81. The method, use, compound, agent, combination or tacrolimus solution of embodiments II-1 to II-6, II-9, II-10 and II-74 to II-79, wherein the cancer is characterized by an increase in mTORC1 activity of 75-80, wherein the cancer comprises greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95% or greater than about 99% clonality of pathogenic variants in one or more of PIK3CA, PTEN, TSC1 and TSC2.

[0531] Embodiment II-82. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-6, II-9, II-10 and II-75 to II-81, wherein the cancer is characterized by increased mTORC1 activity.

[0532] Embodiment II-83. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-6, II-9, II-10 and II-75 to II-82, wherein the cancer is characterized by decreased 4EBP1 activity.

[0533] Embodiment II-84. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-6, II-9, II-10 and II-75 to II-83, wherein the cancer comprises a mutation in the Myc family.

[0534] Embodiment II-85. The method, use, compound, agent, combination and tacrolimus solution according to embodiment II-84, wherein the cancer comprises an amplification of MYC, MYCL, MYCN or a combination thereof and / or a dependence on MYC, MYCL, MYCN or a combination thereof.

[0535] Embodiment II-86. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-1 to II-6, II-9, II-10 and II-75 to II-85, wherein the cancer comprises a mutation in NFE2L2.

[0536] Embodiment II-87. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiments II-1 to II-6, II-9, II-10 and II-75 to II-86, wherein the cancer comprises a BRAF fusion.

[0537] Embodiment II-88. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of Embodiments II-1 to II-6, II-9, II-10 and II-75 to II-87, wherein the cancer comprises KRAS G12C mutation.

[0538] Embodiment II-89. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of Embodiments II-1 to II-6, II-9, II-10 and II-75 to II-88, wherein the cancer comprises a co-occurring KRAS G12C and STK11 mutations.

[0539] Embodiment II-90. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of Embodiments II-1 to II-6, II-9, II-10 and II-75 to II-89, wherein the cancer comprises a co-occurring KRAS G12C and PIK3CA E545K mutation.

[0540] Embodiment II-91. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-75 to II-90, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer and rhabdomyosarcoma.

[0541] Embodiment II-92. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-5, II-9, II-10 and II-75 to II-91, wherein the cancer is a solid tumor.

[0542] Embodiment II-93. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-5, II-9, II-10 and II-75 to II-02, wherein the cancer is head and neck cancer.

[0543] Embodiment II-94. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-5, II-9, II-10 and II-75 to II-93, wherein the cancer is salivary gland cancer.

[0544] Embodiment II-95. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-75 to II-92, wherein the cancer is colorectal cancer and comprises a mutation of PIK3CA, an amplification of MYC, or a mutation of PIK3CA and an amplification of MYC.

[0545] Embodiment II-96. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-75 to II-92, wherein the cancer is head and neck cancer and comprises a mutation in PIK3CA, a mutation in PTEN, or a mutation in PIK3CA and a mutation in PTEN.

[0546] Embodiment II-97. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-75 to II-92, wherein the cancer is hepatocellular carcinoma and comprises a mutation in NFE2L2.

[0547] Embodiment II-98. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-75 to II-92, wherein the cancer is ovarian cancer and comprises a mutation in TSC2.

[0548] Embodiment II-99. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions according to embodiments II-1 to II-5, II-9, II-10 and II-75 to II-92, wherein the cancer is pancreatic cancer and comprises a mutation in STK11, KRAS G12C Mutation or mutation of STK11 and KRAS G12C mutation.

[0549] Embodiment II-100. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-75 to II-92, wherein the cancer is prostate cancer and comprises a mutation in PTEN.

[0550] Embodiment II-101. The methods, uses, compounds, agents, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-75 to II-92, wherein the cancer is uterine cancer and comprises a mutation of PIK3CA, a mutation of PIK3CA, a mutation of TSC2 or a combination thereof.

[0551] Embodiment II-102. The methods, uses, compounds, medicaments, combinations and tacrolimus solutions of embodiments II-1 to II-5, II-9, II-10 and II-72 to II-92, wherein the cancer is lung cancer and comprises a BRAF fusion.

[0552] Embodiment II-103. The method, use, compound, medicament, combination and tacrolimus solution according to embodiments II-1 to II-102, wherein the method results in tumor regression.

[0553] Embodiment II-104. The method, use, compound, medicament, combination and tacrolimus solution according to embodiments II-1 to II-103, wherein the method results in apoptosis of tumor cells. Example

[0554] The following examples are provided to illustrate the present disclosure and should not be construed as limiting thereof. Example 1 - Primary Pharmacodynamics In vitro studies

[0555] RMC-5552 was characterized in vitro using standard biochemical and cellular assays to determine the mode of interaction with mTORC1 and mTORC2. The effects of RMC-5552 on established cellular readouts of mTORC1 activity (including phosphorylation of P70S6K at Thr389 and 4EBP1 at Thr37 / 46), mTORC2 activity (including phosphorylation of Akt at Ser473), and cell proliferation were monitored.

[0556] RMC-5552 binds to the intracellular protein FKBP12 and engages the FRB allosteric site and the ATP binding site on the mTORC1 complex, resulting in inhibition of mTOR kinase activity. In human cancer cell lines, RMC-5552 effectively inhibits the phosphorylation of P70S6K and 4EBP1, and the IC 50The values ​​ranged from 0.13nM to 0.51nM and 0.48nM to 2.4nM, respectively. Cell-selective inhibition of mTORC1 over mTORC2 is defined as the potency ratio of inhibiting phosphorylation of 4EBP1 to inhibiting phosphorylation of Akt, ranging from 15.8-fold to 38.9-fold. In human, mouse and rat cells, RMC-5552 exhibited similar inhibitory potency for mTORC1 and selectivity over mTORC2. Inhibition of mTORC1 by RMC-5552 resulted in inhibition of cell proliferation, with potency ranging from 0.05 to 0.56nM in cell lines with activating mutations in the PI3K / mTOR pathway, and from 0.10 to 0.46nM in HNSCC cell lines. In vivo studies

[0557] The anti-tumor activity of RMC-5552 as a single agent was evaluated in selected CDX and / or PDX models against tumors predicted to be dependent on the mTOR pathway and / or harboring specific PI3K / mTOR pathway activating mutations (i.e., PIK3CA mut , phosphatase and tensin homolog [PTEN LOF ], or co-mutations of both and tuberous sclerosis complex [TSC LOF ]).

[0558] Table 1. RMC-5552 was administered intraperitoneally once a week at 1, 3, 10 and 30 mg / kg in breast cancer MCF7PIK3CA E545K A higher dose of 50 mg / kg once weekly and an alternating dose regimen of 30 mg / kg every 10 days were also evaluated in the model.

[0559] In vivo PK-pharmacodynamic relationships of RMC-5552 as a single agent for inhibition of activated mTOR pathway signaling were determined in the breast cancer MCF7 and HCC-1954 PIK3CA mutant CDX models.

[0560] In solid tumor CDX or PDX models representing various human cancers with genotypic aberrations driving activated mTOR signaling, weekly intraperitoneal administration of RMC-5552 at doses as low as 1 mg / kg produced significant TGI; robust antitumor activity was observed at doses of 3 mg / kg and 10 mg / kg (and 30 mg / kg was tested), and tumor regression was evident in some models (summarized in

[0561] PIK3CA in Table 1 and Fig. 1 mut CDX model of breast cancer, PIK3CA in Figure 2 mut PTEN mutRepresentative results of CDX models of ovarian cancer and PDX models of HNSCC in Figure 3 ).

[0562] These doses and schedules were generally well tolerated in all models. In xenograft models of 2 different human cancers with mTOR pathway activating mutations (i.e., ovarian and bladder cancer), RMC-5552 treatment resulted in durable responses and significantly delayed tumor regrowth after treatment cessation (see Figure 4 for representative results in the ovarian cancer model).

[0563] Consistent with inhibition of mTORC1 signaling in vitro, intraperitoneal administration of RMC-5552 to nude mice produced dose- and plasma concentration-dependent inhibition of tumor p4EBP1 and pS6RP (a direct substrate of P70S6K) in the PI3K mutant breast cancer MCF7 xenograft model. Figure 5 The inhibition of p4EBP1 was maximal 24 to 48 hours after treatment. The half-maximal effective concentration (EC) for inhibition of p4EBP1 in MCF7 cells was 50 ) was 0.22 nM (unbound), and a maximal inhibition level of >90% relative to the control was observed.

[0564] Interestingly, weekly dosing was effective despite the absence of continuous p4EBP1 inhibition. In summary, the MED of RMC-5552 in murine models of mTORC1-activated cancer was estimated to be between 1 and 3 mg / kg once weekly, which resulted in a mean C of 2.0 to 14.7 nM, respectively. max,u and unbound mean AUCs ranging from 21 to 210 nM x h (adjusted for the concentration-dependent unbound fraction in mouse plasma). Table 1: Antitumor activity of RMC 5552 in solid tumor cell line-derived or patient-derived xenograft models harboring specific activating mutations in the PI3K / mTOR pathway Abbreviations: CDX = cell line-derived xenograft; HNSCC = head and neck squamous cell carcinoma; IP = intraperitoneal; p4EBP1 = phosphorylated eukaryotic translation initiation factor 4E binding protein 1; PDX = patient-derived xenograft; pEGFR = phosphorylated epidermal growth factor receptor; PI3K = phosphatidylinositol 3-kinase; mTOR = mammalian target of rapamycin / mechanistic target of rapamycin; PIK3CA = phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN = phosphatase and tensin homolog; TGI = tumor growth inhibition; TSC1 = tuberous sclerosis complex subunit 1. Note: In all studies, RMC-5552 was administered in a transcutol / solutol-based formulation. Example 2 - Monotherapy Effects in Humans

[0565] The studies used as the basis for the clinical data in this section were conducted in accordance with GCP, in accordance with the requirements of the ICH E6 Good Clinical Practice guideline. These studies also complied with the requirements of the Declaration of Helsinki, standard operating procedures for clinical studies and the sponsor's documentation, applicable national laws and regulations, and the ethical principles of Directive 2001 / 20 / EC.

[0566] RMC-5552 is currently being evaluated as a monotherapy in an FIH, dose-escalation, Phase 1 / 1b study (RMC-5552-001) in adult subjects with advanced relapsed / refractory solid tumors. Detailed information about other research projects See Example 3 for more information. ). The purpose of this study is to evaluate the safety, tolerability, preliminary efficacy, PK and pharmacodynamics of RMC-5552 monotherapy. The primary objective is to characterize the safety and tolerability of RMC-5552 monotherapy and define the MTD and recommended phase 2 dose (RP2DS) and schedule of RMC-5552 monotherapy in subjects with relapsed / refractory solid tumors.

[0567] A total of 39 subjects were treated with RMC-5552 monotherapy at 6 dose levels in a weekly intravenous injection schedule: 1.6 mg via 1 hour infusion (n=2), 3.0 mg via 1 hour infusion (n=3), 6.0 mg via 1 hour infusion (n=12), 8 mg via 1 hour infusion (n=15), 12 mg via 1 hour infusion (n=2), and 10 mg via 2 hours infusion (n=5).

[0568] Of the 27 subjects evaluable for efficacy (who had a post-baseline response assessment or who died or had clinical progression before the first post-baseline response assessment), those who received weekly intravenous 6 mg as their primary dose and those who received weekly intravenous 8 mg as their primary dose, 19 subjects had stable disease as their best response, and one subject had a confirmed partial response with a 77.6% reduction in the RECIST measurement. The disease control rate (DCR) for this group was 74.1%.

[0569] Characterize the plas...

Claims

1. A method of treating a subject having cancer, the method comprising administering to the subject a compound at a dose of about 3 mg / week to about 25 mg / week; The compound or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

2. Use of a compound for treating cancer, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

3. Use of a compound in the manufacture of a medicament for treating cancer, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

4. A compound for use in a method of treating cancer, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

5. A medicament for treating cancer, the medicament comprising a compound, wherein the treatment comprises administering the medicament to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

6. A method of treating a subject having salivary gland cancer, the method comprising administering to the subject a compound at a dose of about 3 mg / week to about 25 mg / week; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

7. A method for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg / week to about 25 mg / week of a compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

8. A method of treating acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg / week to about 25 mg / week of a compound; wherein the compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

9. A compound for use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to the subject a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

10. A combination of a compound and a RAS inhibitor for simultaneous, separate or sequential use in a method of treating cancer in a subject with acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

11. Use of a compound for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the treatment comprising administering to the subject from about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

12. Use of a compound in the manufacture of a medicament for the treatment of delaying or preventing acquired resistance to a RAS inhibitor, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

13. A compound for use in a method of delaying or preventing acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

14. An agent for the treatment of delaying or preventing acquired resistance to a RAS inhibitor, the agent comprising a compound, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof, wherein the subject has received or will receive administration of the RAS inhibitor; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

15. Use of a compound for treating acquired resistance to RAS inhibitors, wherein the treatment comprises administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

16. Use of a compound in the manufacture of a medicament for treating acquired resistance to RAS inhibitors, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

17. A compound for use in a method of treating acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a dose of about 3 mg / week to about 25 mg / week of the compound; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

18. An agent for treating acquired resistance to a RAS inhibitor, the agent comprising a compound, wherein the treatment comprises administering the agent to deliver a dose of about 3 mg / week to about 25 mg / week of the compound to a subject in need thereof; The compound is or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

19. A method of treating or preventing mucositis in a subject who has been, is being, or is to be treated with an mTOR inhibitor, the method comprising administering to the subject a tacrolimus solution.

20. Use of a tacrolimus solution in a method for treating or preventing mucositis, wherein the treatment comprises administering the tacrolimus solution to a subject who has been, is being or is to be treated with an mTOR inhibitor.

21. Use of a tacrolimus solution in the manufacture of a medicament for treating or preventing mucositis, wherein the treatment comprises administering the medicament to a subject who has been, is being or is to be treated with an mTOR inhibitor.

22. A tacrolimus solution for use in a method of treating or preventing mucositis, the method comprising administering the tacrolimus solution to a subject who has been, is being or is to be treated with an mTOR inhibitor.

23. An agent for treating or preventing mucositis, the agent comprising a tacrolimus solution, wherein the treatment comprises administering the agent to a subject who has been, is being or is to be treated with an mTOR inhibitor.

24. The method, the use, the tacrolimus solution or the medicament according to any one of claims 19 to 23, wherein the mucositis is stomatitis.

25. The method, use, tacrolimus solution or medicament according to any one of claims 19 to 24, wherein the mTOR inhibitor is everolimus, sirolimus and albumin-bound sirolimus or a combination of the foregoing.

26. The method, use, tacrolimus solution or medicament according to any one of claims 19 to 24, wherein the mTOR inhibitor has the structure Compounds or a stereoisomer, a tautomer or an oxirane isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing.

27. The method, use, tacrolimus solution or medicament of claim 26, wherein the subject is administered a dose of about 3 mg / week to about 25 mg / week of the compound or its stereoisomer, tautomer or oxirane isomer, or a pharmaceutically acceptable salt of any of the foregoing.

28. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-18 and 27, wherein the dosage is about 4 mg / week to about 25 mg / week, about 4 mg / week to about 14 mg / week, about 4 mg / week to about 12 mg / week, about 5 mg / week to about 25 mg / week, about 5 mg / week to about 14 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 6 mg / week to about 25 mg / week, about 6 mg / week to about 12 mg / week, about 6 ...5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week, about 7 mg / week to about 25 mg / week, about 7 mg / week to about 14 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 25 mg / week, about 8 mg / week to about 14 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week.

29. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-18, 27 and 28, wherein the dosage is about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week.

30. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-18 and 27-30, wherein the dose in the first 1, 2, 3, 4 or 5 weeks is higher than the dose in subsequent weeks.

31. The method, use, compound, medicament, combination or tacrolimus solution of claim 30, wherein the dosage for the first 1, 2, 3, 4 or 5 weeks is about 6 mg / week to about 25 mg / week, about 6 mg / week to about 20 mg / week, about 6 mg / week to about 16 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 8 mg / week to about 25 mg / week. / week, about 8 mg / week to about 20 mg / week, about 8 mg / week to about 16 mg / week, about 8 mg / week to about 14 mg / week, about 8 mg / week to about 12 mg / week, about 8 mg / week to about 10 mg / week, about 10 mg / week to about 25 mg / week, about 10 mg / week to about 20 mg / week, about 10 mg / week to about 16 mg / week, about 10 mg / week to about 14 mg / week, or about 10 mg / week to about 12 mg / week.

32. The method, use, compound, medicament, combination or tacrolimus solution of claim 30 or 31, wherein the dose for the first 1, 2, 3, 4 or 5 weeks is about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week.

33. The method, use, compound, medicament, combination or tacrolimus solution according to any one of claims 30-32, wherein the dose in the first week is higher than the dose in subsequent weeks.

34. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 30-33, wherein the doses in the first 1, 2, 3, 4 or 5 weeks are not administered 1, 2, 3, 4 or 5 weeks later.

35. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 30-34, wherein the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks is about 3 mg / week to about 12 mg / week, about 3 mg / week to about 10 mg / week, about 3 mg / week to about 8 mg / week, about 3 mg / week to about 6 mg / week, about 4 mg / week to about 12 mg / week, about 4 mg / week to about 10 mg / week, about 4 mg / week to about 8 mg / week, about 4 mg / week to about 6 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 8 mg / week, about 5 mg / week to about 6 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 6 mg / week to about 8 mg / week, about 6 mg / week to about 7 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 10 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week.

36. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 30-35, wherein the dose after 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks is about 3 mg / week, about 3.5 mg / week, about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week or about 10 mg / week.

37. The method, use, compound, medicament, combination or tacrolimus solution according to any one of claims 30 to 36, wherein: The dosage for the first 1, 2, 3, 4 or 5 weeks is from about 6 mg / week to about 25 mg / week, from about 6 mg / week to about 20 mg / week, from about 6 mg / week to about 16 mg / week, from about 6 mg / week to about 14 mg / week, from about 6 mg / week to about 12 mg / week, from about 6 mg / week to about 10 mg / week, from about 8 mg / week to about 25 mg / week, from about 8 mg / week to about 20 mg / week, from about 8 mg / week to about 16 mg / week, from about 8 mg / week to about 14 mg / week, from about 8 mg / week to about 12 mg / week, from about 8 mg / week to about 10 mg / week, from about 10 mg / week to about 25 mg / week, from about 10 mg / week to about 20 mg / week, from about 10 mg / week to about 16 mg / week, from about 10 mg / week to about 14 mg / week, or from about 10 mg / week to about 12 mg / week; No administration for 0, 1, 2, 3, 4, or 5 weeks thereafter; Subsequent doses are about 3 mg / week to about 12 mg / week, about 3 mg / week to about 10 mg / week, about 3 mg / week to about 8 mg / week, about 3 mg / week to about 6 mg / week, about 4 mg / week to about 12 mg / week, about 4 mg / week to about 10 mg / week, about 4 mg / week to about 8 mg / week, about 4 mg / week to about 6 mg / week, about 5 mg / week to about 12 mg / week, about 5 mg / week to about 10 mg / week, about 5 mg / week to about 12 mg / week. / week to about 8 mg / week, about 5 mg / week to about 6 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 10 mg / week, about 6 mg / week to about 8 mg / week, about 6 mg / week to about 7 mg / week, about 7 mg / week to about 12 mg / week, about 7 mg / week to about 10 mg / week, about 7 mg / week to about 8 mg / week, about 8 mg / week to about 12 mg / week, or about 8 mg / week to about 10 mg / week.

38. The method, use, compound, medicament, combination or tacrolimus solution according to any one of claims 30 to 37, wherein: The dosage for the first 1, 2, 3, 4 or 5 weeks is about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week; No administration for 0, 1, 2, 3, 4, or 5 weeks thereafter; Subsequent doses are about 3 mg / week, about 3.5 mg / week, about 4 mg / week, about 4.5 mg / week, about 5 mg / week, about 5.5 mg / week, about 6 mg / week, about 6.5 mg / week, about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, or about 10 mg / week.

39. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-18 and 27-38, wherein the dose is administered via intravenous infusion.

40. The method, use, compound, medicament, combination or tacrolimus solution of claim 39, wherein the dose is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours.

41. The method, use, compound, medicament, combination or tacrolimus solution of claim 38 or 40, wherein the dose is administered over about 1 hour.

42. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-41, wherein the subject is a human.

43. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-42, wherein the method further comprises administering a dexamethasone solution to the subject.

44. The method, use, compound, medicament, combination or tacrolimus solution of claim 43, wherein the dexamethasone solution comprises about 0.5 mg / 5 mL dexamethasone.

45. The method, use, compound, medicament, combination or tacrolimus solution of claim 43 or 44, wherein about 2.5 mL of the dexamethasone solution is administered to the subject.

46. ​​The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 43-45, wherein the dexamethasone solution is administered 1, 2, 3 or 4 times daily.

47. The method, use, compound, agent or combination of any one of claims 1-18 and 28-46, wherein the method further comprises administering a tacrolimus solution to the subject.

48. The method, use, compound, agent or combination according to 47, wherein the tacrolimus solution comprises about 0.1 mg / mL to about 1 mg / mL.

49. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 19-27, 47 and 48, wherein the tacrolimus solution comprises about 0.1 mg / mL tacrolimus.

50. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 19-27 and 47-49, wherein about 2.5 mL of the tacrolimus solution is administered to the subject.

51. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 19-27 and 47-50, wherein the tacrolimus solution is administered 1, 2, 3 or 4 times daily.

52. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 19-27 and 47-51, wherein the tacrolimus solution is administered on the day of or immediately before the dose.

53. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-52, wherein the method further comprises administering a combined solution to the subject, wherein the combined solution comprises dexamethasone and tacrolimus.

54. The method, use, compound, medicament, combination or tacrolimus solution of claim 53, wherein the combined solution comprises about 0.5 mg / 5 mL dexamethasone.

55. The method, use, compound, medicament, combination or tacrolimus solution of claim 53 or 54, wherein the combined solution comprises about 0.5 mg / mL tacrolimus.

56. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 53-55, wherein about 2.5 mL of the combined solution is administered to the subject.

57. The method, use, compound, medicament, combination or tacrolimus solution according to any one of claims 53-56, wherein the combined solution is administered 1, 2, 3 or 4 times daily.

58. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 53-57, wherein the combined solution is administered on the day of or immediately before the dose.

59. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-58, wherein the method further comprises applying ice to the oral cavity of the subject.

60. The method, use, compound, medicament, combination or tacrolimus solution of claim 59, wherein the ice is applied for about 10 minutes before administering the dose, during administering the dose, and for about 10 minutes after administering the dose.

61. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 27 and 43-60, wherein the dosage is about 6 mg / week to about 25 mg / week, about 6 mg / week to about 20 mg / week, about 6 mg / week to about 16 mg / week, about 6 mg / week to about 14 mg / week, about 6 mg / week to about 12 mg / week, about 6 mg / week to about 9 mg / week, about 6 mg / week to about 8 mg / week or about 7 mg / week to about 8 mg / week.

62. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 27 and 43-61, wherein the dosage is about 7 mg / week, about 7.5 mg / week, about 8 mg / week, about 8.5 mg / week, about 9 mg / week, about 9.5 mg / week, about 10 mg / week, about 10.5 mg / week, about 11 mg / week, about 11.5 mg / week, about 12 mg / week, about 12.5 mg / week, about 13 mg / week, about 13.5 mg / week, about 14 mg / week, about 14.5 mg / week, about 15 mg / week, about 16 mg / week, about 18 mg / week, about 20 mg / week, about 22 mg / week or about 25 mg / week.

63. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-62, wherein the method further comprises administering a RAS inhibitor to the subject.

64. The method, use, compound, medicament, combination or tacrolimus solution of claim 63, further comprising administering to the subject an effective amount of the RAS inhibitor.

65. The method, use, compound, medicament, combination or tacrolimus solution of claim 63 or 64, wherein the RAS inhibitor targets a specific RAS mutation.

66. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 63-65, wherein the RAS inhibitor targets a KRAS mutation.

67. The method, use, compound, medicament, combination or tacrolimus solution of claim 65 or 66, wherein the RAS inhibitor targets KRAS G12C mutation.

68. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 63-67, wherein the RAS inhibitor is a KRAS(OFF) inhibitor.

69. The method, use, compound, medicament, combination or tacrolimus solution of claim 68, wherein the KRAS(OFF) inhibitor is AMG 510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255 or a pharmaceutically acceptable salt of any one of the foregoing.

70. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 63-67, wherein the RAS inhibitor is a RAS(ON) inhibitor.

71. The method, use, compound, medicament, combination or tacrolimus solution of claim 70, wherein the RAS(ON) inhibitor is a KRAS(ON) inhibitor.

72. The method, use, compound, medicament, combination or tacrolimus solution of claim 71, wherein the KRAS(ON) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839 or a pharmaceutically acceptable salt of any one of the foregoing.

73. The method, use, compound, medicament, combination or tacrolimus solution of claim 71 or 72, wherein the KRAS(ON) inhibitor is KRAS G12C (ON) inhibitor.

74. The method, use, compound, medicament, combination or tacrolimus solution of claim 72 or 73, wherein the KRAS G12C The (ON) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

75. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 7, 8 and 11-74, wherein the subject has cancer.

76. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75, wherein the cancer is characterized by a genotypic aberration that activates the mammalian target of rapamycin (mTOR) pathway.

77. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10, 75 and 76, wherein the cancer comprises a mutation in the mTOR pathway.

78. The method, use, compound, medicament, combination or tacrolimus solution according to claim 76 or 77, wherein the genotypic aberration or the mutation is a genotypic aberration or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1 or TSC2 or a combination thereof.

79. The method, use, compound, medicament, combination or tacrolimus solution according to any one of claims 76-78, wherein the genotypic aberration or the mutation is a genotypic aberration or mutation of PTEN.

80. The method, use, compound, medicament, combination or tacrolimus solution of claim 79, wherein the PTEN mutation is a dominant negative mutation.

81. The method, use, compound, agent, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-80, wherein the cancer comprises greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95% or greater than about 99% clonality of pathogenic variants in one or more of PIK3CA, PTEN, TSC1 and TSC2.

82. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-81, wherein the cancer is characterized by increased mTORCl activity.

83. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-82, wherein the cancer is characterized by decreased 4EBP1 activity.

84. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-83, wherein the cancer comprises a mutation in the Myc family.

85. The method, use, compound, medicament, combination or tacrolimus solution of claim 84, wherein the cancer comprises an amplification of and / or a dependency on MYC, MYCL, MYCN or a combination thereof.

86. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-85, wherein the cancer comprises a mutation in NFE2L2.

87. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 74-85, wherein the cancer comprises a BRAF fusion.

88. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-87, wherein the cancer comprises KRAS G12C mutation.

89. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-88, wherein the cancer comprises a co-occurring KRAS G12C and STK11 mutations.

90. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-6, 9, 10 and 75-89, wherein the cancer comprises a co-occurring KRAS G12C and PIK3CA E545K mutation.

91. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-90, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer and rhabdomyosarcoma.

92. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-91, wherein the cancer is a solid tumor.

93. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 74-92, wherein the cancer is head and neck cancer.

94. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-93, wherein the cancer is salivary gland cancer.

95. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-92, wherein the cancer is colorectal cancer and comprises a mutation of PIK3CA, an amplification of MYC, or a mutation of PIK3CA and an amplification of MYC.

96. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-92, wherein the cancer is head and neck cancer and comprises a mutation in PIK3CA, a mutation in PTEN, or a mutation in PIK3CA and a mutation in PTEN.

97. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-92, wherein the cancer is hepatocellular carcinoma and comprises a mutation in NFE2L2.

98. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-92, wherein the cancer is ovarian cancer and comprises a mutation in TSC2.

99. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-92, wherein the cancer is pancreatic cancer and comprises a mutation in STK11, KRAS G12C Mutation or mutation of STK11 and KRAS G12C mutation.

100. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 74-91, wherein the cancer is prostate cancer and comprises a mutation in PTEN.

101. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-92, wherein the cancer is uterine cancer and comprises a mutation of PIK3CA, a mutation of PIK3CA, a mutation of TSC2 or a combination thereof.

102. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-5, 9, 10 and 75-92, wherein the cancer is lung cancer and comprises a BRAF fusion.

103. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-102, wherein the method results in tumor regression.

104. The method, use, compound, medicament, combination or tacrolimus solution of any one of claims 1-103, wherein the method results in apoptosis of tumor cells.

Images