Biomarkers for patient selection for treatment with a translation elongation inhibitor

Abstract

Methods for treating or ameliorating abnormal cell proliferative disorders, such as cancer, through the administration of a translation elongation inhibitor, as well as biomarkers to determine if a patient will respond, or not respond to treatment by the same.

Description

[0001] BIOMARKERS FOR PATIENT SELECTION FOR TREATMENT WITH A TRANSLATION ELONGATION INHIBITOR CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This International PCT Application claims the benefit of and priority to U.S. Provisional Application No. 63 / 770,325 filed March 11, 2025, the specification, claims and drawings of which are incorporated herein by reference in their entirety.

[0003] STATEMENT OF GOVERNMENT INTEREST

[0004] This invention was made with government support under grant numbers R01 GM106317 and R35 GM 130374 awarded by the National Institute of Health. The government has certain rights in the invention.

[0005] TECHNICAL FIELD

[0006] The present disclosures is directed to methods for treating or ameliorating abnormal cell proliferative disorders, such as cancer, through the administration of a translation elongation inhibitor, as well as biomarkers to determine if a patient will respond, or not respond to treatment by the same.

[0007] BACKGROUND

[0008] Growth, proliferation and survival of cancer cells rely upon the continuous presence of unstable cancer driver proteins such as c-Myc, Cyclin DI and MCL-1. Consequently, protein synthesis inhibitors have long been hypothesized to have therapeutic potential in cancer as blocked synthesis would lead to the depletion of unstable cancer driver proteins according to their intrinsic instability. Two inhibitors of protein synthesis are FDA-approved for cancer, and both inhibit the elongation step of translation. Denileukin diftitox (Ontak®), an interleukin-2 (IL-2) and diphtheria toxin (DT) conjugate, which acts by ADP-ribosylating and inhibiting Elongation Factor 2 (EF2), a GTPase and an accessory factor for the ribosome. DT is highly toxic but replacing the endogenous targeting sequences with the IL-2 moiety to re-target it to CD25+ cancer cells sufficiently improved safety for FDA approval in Cutaneous T-cell lymphoma (CTCL). Homoharringtonine (HHT), also known as Omacetaxine mepesuccinate (Synribo®), inhibits translation elongation by interacting with the ribosome A site. It is approved for the treatment of chronic myeloid leukemia (CML) patients with resistance to two or more tyrosine kinase inhibitors. Both Ontak / DT and HHT are thought to show little specificity in mRNAs whose translation that they inhibit and thereby the proteins that are depleted, which could explain theirnoted toxicity. Recent efforts to identify more selective and, therefore, less toxic inhibitors of protein synthesis have yielded inhibitors of translation initiation factors eIF4A and eIF4E. Several have entered the clinical pipeline and are in early clinical trials (e.g., NCT04092673, NCT01234038, NCT01179542), but none are FDA-approved. Therefore, protein translation remains a promising but under-utilized target area for therapeutic intervention in oncology.

[0009] Applicant previously described SVC112, a fully synthetic small molecule inhibitor of translation elongation. It is a proprietary derivative of Bouvardin (NSC259968), a plant-derived bicyclic hexapeptide that Applicants found in a screen for inhibitors of tissue regeneration (See U.S. Patent No’s 9,452,215, and 10259846, incorporated herein by reference). The screen was designed to identify molecules that show greater efficacy on p53 and Chkl mutant tissues compared to wild type 10, thereby favoring the identification of molecules that preferentially target cancerous growth and providing potential for good therapeutic index. SVC 112 and Bouvardin exhibit a first-in-class mechanism of action (MoA) that prevents the cyclic dissociation of Elongation Factor 2 (EF2) from the ribosome, thereby inhibiting the elongation step of translation. (See U.S. Patent No’s 9,452,215, and 10259846, incorporated herein by reference) SVC112 suppressed the proliferation of cancer stem cells in Head and Neck Squamous Carcinoma (HNSCC) by depleting the unstable cancer driver c-Myc and the sternness protein Sox2. SVC112 showed tumor growth control when applied after radiation treatment in mouse patient-derived xenograft (PDX) studies, with an acceptable toxicity profile. Further, SVC 112 exhibits greater selectivity on patient-derived HNSCC cells over patient-matched normal cells (Cancer-associated fibroblasts or CAF), suggesting the potential for a good therapeutic index. In contrast, HHT exhibits similar efficacy on cancer and normal cells from the same patient matched pairs, which could explain its observed toxicity in the clinic. SVC112 entered the NCI Experimental Therapeutics (NExT) pipeline in 2023, for development towards the clinic. Here, Applicant report that SVC112’s efficacy is not limited to HNSCC models but extends to hematologic and colorectal cancer models and identify molecular correlates for sensitivity to SVC 112 that can optimize its clinical application.

[0010] SUMMARY OF THE DISCLOSURE

[0011] The present disclosure provides methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient SVC112, or pharmaceutically acceptable salt or solvate thereof. The present disclosure further provides methods of treating a cancer in a patientin need thereof, the method comprising administering to the patient SVC112, or pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from: a hematological cancer, leukemia, gastrointestinal cancer, acute myeloid leukemia (AML), multiple myeloma (Myeloma), and colorectal cancer (CRC).

[0012] The present disclosure further provides methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising SVC 112, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0013] The present disclosure further provides methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising SVC112, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the cancer is selected from: a hematological cancer, leukemia, gastrointestinal cancer, acute myeloid leukemia (AML), multiple myeloma (Myeloma), and colorectal cancer (CRC).

[0014] The present disclosure further provides methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising SVC 112, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from dimethyacetamide (DMA), Cremaphor EL (CrEL), N-methylpyrrolidone (NMP), a cyclodextrin, or a combination thereof.

[0015] The present disclosure further provides methods of treating a cancer in a patient in need thereof, including the step of co-administering to the patient a composition comprising SVC 112, or pharmaceutically acceptable salt or solvate thereof and at least one oncology therapeutic selected from a BCL-2 inhibitor, a BCL-XL inhibitor, and an ERK inhibitor. The present disclosure further provides methods of treating a cancer in a patient in need thereof, including the step of co-administering to the patient a composition comprising SVC 112, or pharmaceutically acceptable salt or solvate thereof and at least one oncology therapeutic selected from radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents.

[0016] This present disclosure provides methods and materials involved in assessing biological samples for the status of biomarkers indicative of cancer patient response to anti-cancertherapeutic regimens. In general, an analysis of the biomarkers can reveal whether a cancer cell is likely sensitive or resistant to treatment with certain anti-cancer compounds, namely transcription elongation factors such as SVC 112. Thus, the present disclosure is generally related to the identification of cancer patients that are predicted to benefit from the therapeutic administration of SVC112.

[0017] The present disclosure further provides methods of treating cancer in a subject in need thereof, including administering to the subject a therapeutically effective amount of a translation elongation inhibitor, such as SCV112, based on the level of at least one biomarker in a biological sample from the subject, wherein the biomarkers are selected from MCL-1, BCL-XL and c-Myc. In one aspect, the level of the biomarker can include the expression level or activity of the biomarker, or in the example of c-Myc, the phosphorylation status of amino acid position 62 (Serine 62 or Ser62).

[0018] The present disclosure further provides methods for determining the sensitivity or resistance of a cancer subject to treatment with an translation elongation inhibitor. In one example, this method includes the steps of obtaining a biological sample from a subject and measuring the level of one or more biomarkers in a biological sample obtained from a subject, wherein the one or more biomarkers is selected from: MCL-1, BCL-XL, and c-Myc, and determining that the patient is: i) sensitive to the treatment if the level of MCL-1 is above a predetermined threshold, or is resistant to the treatment if the level of MCL-1 is below the predetermined threshold; or ii) sensitive to the treatment if the level of BCL-XL is below a predetermined threshold, or is resistant to the treatment if the level of BCL-XL is above the predetermined threshold; or iii) sensitive to the treatment if the level of phosphorylation of c-Myc at position Ser62 is below a predetermined threshold, or is resistant the treatment if the level of phosphorylation of c-Myc at position Ser62 is above the predetermined threshold. Based on the above determination, the method can include administering a therapeutically effective amount of a translation elongation inhibitor, such as SVC112 as well as optionally a second oncology therapeutics, to the subject determined to be sensitive based on the level of the at least one of the biomarkers.

[0019] The present disclosure further provides for a diagnostic kit for determining the sensitivity or resistance of a cancer patient to treatment with a translation elongation inhibitor, namely SVC 112. In a preferred example, the kit includes reagents for detecting and quantifying one or more biomarkers selected from MCL-1, BCL-XL, and c-Myc levels in a biological sample, andinstructions for interpreting the results to determine whether the patient is sensitive or resistant to translation elongation inhibitor based on the biomarker level.

[0020] Additional aspects of the disclosure may include one or more of the preferred embodiments set forth in the claims.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1A-B. SVC112 inhibits new protein synthesis and confers growth inhibition to different extents in different cell lines. (A) Sensitivity to SVC112 varies widely in cancer cell lines representing AML, Myeloma, CRC and HNSCC. Cells were exposed to 10 different drug concentrations (0 to 10 pM) with growth determined after 72 hours (hr) using Cell Titer-Gio. ICso was calculated using non-linear regression. Data shown are averages of 6 technical replicates each in 3 biological replicate experiments. Error bars represent mean ± 1 standard deviation (STD). (B) SVC112 inhibits de novo protein synthesis in representative sensitive cancer cell lines. Cells were grown for Ihr in methionine free media, followed by L-azidohomoalanine (AHA) incorporation for 2 hr in the presence of vehicle or 1 pM SVC112. Incorporated AHA was quantified by click chemistry TRITC labeling and normalized to vehicle controls. AML = acute myeloid leukemia. Myeloma = multiple myeloma. CRC = colorectal cancer. HNSCC = head and neck squamous cell carcinoma.

[0023] Figure 2A-D. The ability of SVC112 to induce apoptosis varies among sensitive cell lines. (A) Induction of PARP cleavage by SVC112 is concomitant with depletion of MCL-1 and Myc in AML but not CRC and HNSCC cell lines. Cells were treated continuously with SVC 112 (IpM for 6 or 24 hr), or transiently for 6 hr followed by drug washout and recovery for 18 hr (‘6-18hr’ lanes). Protein extracts were analyzed by Western blotting for MCL-1, Myc, and PARP with the long-lived protein Nucleolin serving as a loading control. *denotes cleaved PARP. (B-B’) Representative flow cytometry scatter plots (B) showing live-cell Annexin V staining and Propidium iodide (PI) uptake in MV-4-11 (AML) cells following transient SVC 112 treatment (1 pM for 6 hr) followed by drug wash out and recovery for 18 or 42 hr. (B’) Quantification of Annexin VZPI positive cells for each cell line, representing a minimum of 3 biological replicate experiments each. Error bars represent mean ±1STD. (C-C”) Basal (no-treatment) levels of pro-apoptotic and pro-survival proteins analyzed by Western blotting. Protein levels were determined via densitometric quantification in Imaged and assessed with Pearson correlation coefficient (p).(D) Depletion of MCL-1 and Myc by SVC112 in Kasumi-3 AML cell line does not accompany PARP cleavage. Cells were treated as in (A). *denotes cleaved PARP.

[0024] Figure 3A-D. SVC112 shows efficacy in xenografted tumors in mice. (A) MV-4-11 AML cells were implanted into the flank of mice (n=5 / group) and treated via IP injection QDX5 for three weeks with vehicle or 60 mg / kg SVC112. (B-B’) MV-4-11 AML cells were orthotopically inoculated into mice (n=10 / group) and treated via IP injection bi-weekly (Mon / Thur) for three weeks with vehicle or 60 mg / kg SVC112. (C-C”) EOL-1 AML cells were implanted into the flank of mice (n=9 per group) and treated via IV tail vein injection QDX5 for three weeks with vehicle or 5 mg / kg SVC112. Two SVC112-treated mice exhibited full tumor regression at experiment termination. (D-D”) SVC112 inhibits the growth ofHCT116 CRC cells were implanted into the flank of mice (n=9 for vehicle and 10 for SVC112) and treated QDX5 for three weeks with vehicle or 10 mg / kg SVC 112 via IV tail vein injection. Tumor volumes are shown until the first vehicle control tumor exceeded the institutional limit of 2000 mm3. Survival was tracked until animal death or moribundity (B) or until individual tumor volume exceeded 2000 mm3(C’ and D’) and displayed using Kaplan-Meier plots. Error bars represent mean ±1SEM.

[0025] Figure 4A-D’. Myc status and resistance to SVC112 in CRC cell lines. (A) The combination of SVC 112 and Ulixertinib depletes Myc in SVC 112-resistant CRC cells. DLD-1 and SW948 cells were treated with 1 pM of each drug, alone or in combination, for 6 hr and analyzed by Western blotting. (B) Combination Index measurements for drug-drug interaction between SVC112 and Ulixertinib assessed using CellTiter-Glo assay after 72 hr incubation in a 10-dose pairwise combination of drugs ranging from 0 to 10 pM. IC50 was calculated as for Fig. 1. (C-C’) The effect of SVC112 and Ulixertinib on clonogenic growth of DLD-1 cells. Representative images are shown along with quantified averages from 3 biological replicate experiments with two technical replicates each. Expected outcome for additive drug-drug interaction is shown as dashed lines. Error bars represent mean ±1STD. (D) SVC112 / Ulixertinib combination inhibits tumor growth. Mice (n=4 for Ulixertinib and 5 for all other groups) were treated QDX5 for three weeks, with vehicle, 15 mg / kg SVC112, 50mg / kg Ulixertinib or the combination by IP injection. Tumor volumes were recorded until the first tumor exceeded the institutional limit of 2000 mm3and p-values computed for that day. Survival was tracked until individual tumor volume exceeded 2000 mm3and displayed using Kaplan-Meier plots. Error bars represent mean ±1SEM.Figure 5A-C. Comparison of SVC112, HHT and MCL-1 inhibitor S63845. (A) SVC112 and HHT inhibit translation elongation from an uncapped luciferase mRNA template in in vitro in rabbit reticulocyte lysates as detected by luciferase activity. (B) Growth inhibition in select AML and Myeloma cell lines following a 72 hr incubation with MCL-1 inhibitor S63845, SVC112 or HHT. IC50 values calculated as for Fig. 1. (C) Protein depletion by SVC112 and HHT in Peripheral Blood Mononuclear Cells accompanies robust PARP and Caspase 3 cleavage with only HHT. Protein levels were analyzed by Western blotting as in (Figure 2A). Error bars represent mean ±1STD.

[0026] Figure 6A-A”. Survival and body weight measurements in CRC xenografts. Survival was tracked until individual tumor volumes exceeded 2000 mm3. (A-B) Body weight (A) Kaplan-Meier plot for animal survival (B) for the HCT116 xenograft experiment shown in Fig. 3C. Mice (n=9 for vehi cl e and 10forSVC112) were treated QDX5 for three weeks, with vehi cl e or 10 mg / kg solution formulation SVC 112 administered by IV injection into the tail vein. (C) Kaplan-Meier plot for animal survival for the DLD-1 xenografts experiment shown in Fig. 31. Mice (n=4 for Ulixertinib and 5 for all other groups) were treated QDX5 for three weeks, with vehicle, 15 mg / kg SVC112, 50 mg / kg Ulixertinib or the combination administered by IP injection.

[0027] Figure 7. Chemical structure of SVC112.

[0028] DETAILED DESCRIPTION

[0029] Unless defined otherwise, all scientific and technical terms are to be understood as having the same meaning as commonly used in the art to which they pertain.

[0030] As used herein the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes one or more cells and equivalents thereof known to those skilled in the art, and so forth. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Hence “comprising A or B” means including A, or B, or A and B. Furthermore, the use of the term “including”, as well as other related forms, such as “includes” and “included”, is not limiting.

[0031] The term “about” as used herein is a flexible word with a meaning similar to “approximately” or “nearly”. The term “about” indicates that exactitude is not claimed, but rather a contemplated variation. Thus, as used herein, the term “about” means within 1 or 2 standard deviations from the specifically recited value, or ± a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 4%, 3%, 2%, or 1 % compared to the specifically recited value.The disclosure described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of’, and “consisting of’ may be replaced with either of the other two terms.

[0032] As described herein, the compound SVC 112 (Fig. 7) inhibits growth among cancer cell lines of various origins. SVC112 sensitivity analysis identified that basal expression of apoptosis / survival factors correlates with SVC112-induced apoptosis in hematologic cancer cell lines while phosphorylation of c-Myc at position Ser62 correlates with sensitivity to SVC112 in colorectal cancer cell lines. Unless indicated otherwise, all references herein to small molecule SVC112 include references to pharmaceutically acceptable salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of pharmaceutically acceptable salts thereof, and include amorphous and polymorphic forms, stereoisomers, and isotopically labeled versions thereof.

[0033] In one embodiment, the disclosure provides a method for treating a disease or disorder, and preferably cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an transcription elongation inhibitor. As used herein, “elongation translation inhibitor” refers to any molecule that partially or fully inhibits the activity of translation with a cell. As used here “inhibition,” “inhibit,” or “depletion” are used interchangeably to denote the down-regulation of the expression or activity or level of phosphorylation relative to its normal level in a wild type environment. Suppression includes expression that is decreased by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to the wild type level. In one embodiment, SVC112 is elongation translation inhibitor. SVC112 shown in Figure 7 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. See Keysar SB, et al. Inhibiting Translation Elongation with SVC 112 Suppresses Cancer Stem Cells and Inhibits Growth in Head and Neck Squamous Carcinoma. Cancer Res. 2020 Mar l;80(5): 1183-1198; See also U.S. Patent No. 9,452,215 (incorporated herein by reference).

[0034] In one embodiment, the disclosure provides a method for treating a disease or disorder, and preferably cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the transcription elongation inhibitor SVC 112. In one embodiment, the disclosure further provides therapeutic methods and uses comprising administering SVC112, orpharmaceutically acceptable salts thereof, alone or in combination with one or more other therapeutic agents or palliative agents.

[0035] The present disclosure provides methods of treating a cancer in a patient in need thereof, the method comprising administering to the patient SVC112, or pharmaceutically acceptable salt or solvate thereof, wherein the cancer can include solid tumor or hematological cancers, including but not limited to multiple myeloma, gastrointestinal cancer, salivary gland cancer, or leukemia.

[0036] In another embodiment, The present disclosure provides methods of treating a leukemia in a patient in need thereof, the method including administering to the patient SVC112, or pharmaceutically acceptable salt or solvate thereof. In this embodiment, the leukemia to be treated is selected from acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or chronic myelomonocytic leukemia (CMML).

[0037] In another embodiment, the present disclosure provides methods of treating AML in a patient in need thereof, the method including administering to the patient a therapeutically effective amount of SVC 112, or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a therapeutically effective amount of SVC112, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In this embodiment, the AML is characterized as having an oncogenic alteration selected from: TP53, FLT3, MLL fusion, CDKN2A, NRAS, DNMT3A, NPM1, or any combination thereof. In one embodiment, the oncogenic CDKN2A alteration includes a CDKN2A P84 mutation, and wherein the CDKN2A P84 mutation comprises a P84L substitution. In another embodiment, the oncogenic NRAS alteration is a NRAS Q61L mutation. In another embodiment, the oncogenic DNMT3A alteration is a DNMT3 A R882C mutation. In another embodiment, the oncogenic NPM1 alteration is a NPM1 W288C mutation.

[0038] As used herein, an “oncogenic alteration” or “oncogenic mutation” describes a mutation that may be associated with, or causative of, cancer.

[0039] In another embodiment, the present disclosure provides methods of treating a multiple myeloma in a patient in need thereof, the method including administering to the patient SVC 112, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a therapeutically effective amount of SVC 112, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In this embodiment, the multiplemyeloma to be treated is selected from light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, IgD myeloma, or IgE myeloma. In another embodiment, the multiple myeloma is characterized as having an oncogenic alteration selected from: NRAS, TP53, PIK3CA, EGFR, KRAS, TRAF3, CDKN2A, FGFR3, SMAD2, BRAF, MSH6, or any combination thereof alteration, or any combination thereof. In another embodiment, the oncogenic NRAS alteration is a NRAS G13D mutation, a NRAS Q61H mutation, or any combination thereof. In another embodiment, the oncogenic TP53 alteration is a TP53 A161T mutation, a TP53 R175H mutation, a TP53 S261T mutation, a TP53 E285L mutation, or any combination thereof. In another embodiment, the oncogenic PIK3CA alteration is a PIK3CA E545K mutation. In another embodiment, the oncogenic EGFR alteration is an EGFR T751I mutation. In another embodiment, the oncogenic KRAS alteration is a KRAS G12A mutation. In another embodiment, the oncogenic TRAF3 alteration is a TRAF3 K191L mutation, a TRAF3 K550L mutation, or any combination thereof. In another embodiment, the oncogenic CDKN2A alteration is a CDKN2A H83Y mutation. In another embodiment, the oncogenic FGFR3 alteration is a FGFR3 K650E mutation. In another embodiment, the oncogenic SMAD2 alteration is a SMAD2 L87R mutation. In another embodiment, the oncogenic BRAF alteration is selected from a Class I BRAF mutation, a Class II BRAF mutation, a Class III BRAF mutation, or a BRAF K601N mutation. In another embodiment, the oncogenic MSH6 alteration is a MSH6 G141D mutation.

[0040] In another embodiment, the present disclosure provides methods of treating a gastrointestinal cancer in a patient in need thereof, the method including administering to the patient SVC 112, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a therapeutically effective amount of SVC 112, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In this embodiment, the gastrointestinal cancer to be treated is selected from colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, and esophageal cancer. In another embodiment, the colorectal cancer is colorectal adenocarcinoma. In another embodiment, the gastrointestinal cancer is characterized as having an oncogenic alteration selected from: APC, ACVR2A, KRAS, TP53, PIK3CA, BRAF, TGFBR2, CDKN2A, BRCA2, CTNNB1, PPM ID, EP300, SMAD4, or any combination thereof. In another embodiment, the oncogenic APC alteration is a APC R856Cmutation, a APC T1556N mutation, a APC R2714C mutation, or any combination thereof. In another embodiment, the oncogenic ACVR2A alteration is a ACVR2A K437R mutation. In another embodiment, the oncogenic KRAS alteration is a KRAS G13D mutation. In another embodiment, the oncogenic TP53 alteration is a TP53 S127P mutation, a TP53 K382N mutation, or any combination thereof. In another embodiment, the oncogenic PIK3CA alteration is a PIK3CA P499T mutation, a PIK3CA H1047R mutation, or any combination thereof. In another embodiment, the oncogenic BRAF alteration is selected from a Class I BRAF mutation, a Class II BRAF mutation, a Class III BRAF mutation, or a BRAF V600E mutation. In another embodiment, the oncogenic In another embodiment, the oncogenic TGFBR2 alteration is a TGFBR2 K128S mutation, a TGFBR2 L453P mutation, or any combination thereof. In another embodiment, the oncogenic CDKN2A alteration is a CDKN2A R24S mutation, a CDKN2A E33R mutation, or any combination thereof. In another embodiment, the oncogenic BRCA2 alteration is a BRCA2 I2675N mutation. In another embodiment, the oncogenic EP300 alteration is a EP300 M147S mutation, aEP300 N1700T mutation, or any combination thereof

[0041] In another embodiment, the present disclosure provides methods of treating a metastatic cancer in a patient in need thereof, the method including administering to the patient SVC112, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a therapeutically effective amount of SVC 112, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In one embodiment, treatment of a metastatic cancer can further include treatment selected from: adjuvant therapy following surgical resection, adjuvant therapy to radiotherapy, therapeutic intervention where the patient has relapsed after prior therapy or has acquired resistance to prior therapy, or where the patient is refractory to prior therapy.

[0042] In another embodiment, the present disclosure provides methods of treating a metastatic cancer in a patient in need thereof, the method including administering to the patient SVC112, or a pharmaceutically acceptable salt or solvate thereof, and at least one oncology therapeutic selected from a BCL-2 inhibitor, a BCL-XL inhibitor, and an ERK inhibitor. In one embodiment, the BCL-2 inhibitor is venetoclax. In another embodiment, the ERK inhibitor is ulixertinib.

[0043] Notably, there are a variety of Bcl-2 inhibitors, all of which have the same property of inhibiting the survival-promoting component of the Bcl-2 family of proteins and are therefore promising candidates for cancer treatment. Such Bcl-2 inhibitors are, for example, oblimersen,SPC-2996, RTA-402, gosipor, AT-101, obatoclax mesylate, A-371191, A-385358, A-438744, ABT-737, ABT-263 (Navitoclax), AT-101, BL-11, BL-193, GX-15-003, 2-methoxyantimycin A3, HA-14-1, KF-67544, purpurogallin, TP-TW- 37, YC-137 and Z-24, eg Zhai, D.I. , Et al. , Cell Death and Difference 13 (2006) 1419-1421.

[0044] Binding between cancer and other Bcl-2 family proteins has also been well established and demonstrated in detail (Strasser, A. 2011EMBO J.30, 3667-3683), as well as inhibitors of other Bel family proteins. It is known. Bcl-XL-selective inhibitors A-11554363 and A-1331852 are described, for example, in Leverson et al. It is described in Science Transitional Medicine Vol7, Issue279279ra40. Bcl-XL selective thiazole hydrazone inhibitors are described in Sleeps et al. J. Med. Chem. It is disclosed in 2013, 56, 5514-5540. For other explanations from other Bcl-XL inhibitors, see, eg, Koehler et al. , ACS Med. Chem. Let. 2014, 5, 662-667 and Tao et al, ACS Med. Chem. ett. See 2014, 5, 1088-10. MCLl inhibitors and their use for the treatment of cancer are described, for example, in Leverson et al. , Cell Death and Disease (2015) 6, el590, Brunko et al. , J. Med. Chem. 2015, 58, 2180-2194, Petros et al. , Bioorganic & Medical Chemistry Letters24 (2014) 1484-1488, Abulwardi et al. , Mol Cancer The 2014, 13: 565-5, Abulwerdi et al. , J. Med. Chem. 2014, 57, 4111-4133, Burke et al. , J. Med. Chem. 2015, 58, 3794-3805, Friberg et al. , J. Med. Chem. 2013, 56, 15-30 and belmar et al. , Pharmacology & Therapeutics 145 (2015) 76-84. Mcl-1 / Bcl-xL double inhibitors are available from Tanaka et al. , J. Med. Chem. It is disclosed in 2013, 56, 9635-9645.

[0045] In certain embodiments, the co-treatment of SVC 112 with at least one other oncology therapeutic can be used to treat leukemia, including chronic lymphocytic leukemia (CLL), hairy cell leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or chronic myelomonocytic leukemia (CMML), as well as acute myeloid leukemia (AML). In some embodiment, the leukemia to be treated is characterized as having an oncogenic TP53, FLT3, MLL fusion, CDKN2A, NRAS, DNMT3A, NPM1 alteration, or any combination thereof as described herein.

[0046] In certain embodiments, the co-treatment of SVC 112 with at least one other oncology therapeutic can be used to treat multiple myeloma, including light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, IgD myeloma, or IgE myeloma. In some embodiment, the multiple myeloma to be treated is characterized as having anoncogenic NRAS, TP53, PIK3CA, EGFR, KRAS, TRAF3, CDKN2A, FGFR3, SMAD2, BRAF, MSH6 alteration, or any combination thereof as described herein.

[0047] In certain embodiments, the co-treatment of SVC 112 with at least one other oncology therapeutic can be used to treat gastrointestinal cancer, including colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, and esophageal cancer. In another embodiment, the colorectal cancer is colorectal adenocarcinoma. In some embodiment, the gastrointestinal cancer to be treated is characterized as having an oncogenic APC, ACVR2A, KRAS, TP53, PIK3CA, BRAF, TGFBR2, CDKN2A, BRCA2, CTNNB1, PPM1D, EP300, SMAD4 alteration, or any combination thereof as described herein as described herein.

[0048] As noted above, the present disclosure further provides pharmaceutical compositions, and methods of making a pharmaceutical composition comprising admixing SVC112 together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials, as described herein. Additional therapeutic compounds, such as oncology therapeutics can be included in a pharmaceutical composition.

[0049] As used herein, “pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and / or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (19th Edition). The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

[0050] The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, “Handbook ofPharmaceutical Additives”, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, N.Y., USA), “Remington's Pharmaceutical Sciences”, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and “Handbook of Pharmaceutical Excipients”, 2nd edition, 1994.

[0051] In one embodiment, the disclosures includes methods and compositions for the intravenous administration of SVC 112, or pharmaceutically acceptable salt or solvate thereof. In another embodiment, the disclosures includes methods and compositions for the intravenous administration of pharmaceutical composition suitable for intravenous administration including SVC112, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In one example, a pharmaceutically acceptable excipient is selected from dimethyacetamide (DMA), Cremaphor EL (CrEL), N-methylpyrrolidone (NMP), a cyclodextrin, or a combination thereof. In one particular example, intravenous formulation for the pharmaceutical composition can include DMA and CrEL in a saline solution of a concentration of about .5% to about 1.5% DMA, or in a preferred embodiment about 0.45% to about 1.35% DMA. In another particular example, intravenous formulation for the pharmaceutical composition can include DMA and CrEL in about a 2:1 ratio in a saline solution of a concentration of about .5 to 1.5% DMA, inclusive of all points within any of the above described ranges.

[0052] As used herein, a “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0053] Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Hence, the terms “chemical entity” and “chemical entities” also encompass pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures.

[0054] “Pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which are not biologically or otherwiseundesirable. In many cases, the compounds described herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, futnaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0055] “Solvate” refers to a compound (e.g., a compound selected from Formula I or a pharmaceutically acceptable salt thereof) in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that “a compound of Formula I” encompasses the compound of Formula I and solvates of the compound, as well as mixtures thereof.

[0056] “Therapeutically effective amount” or “effective amount” refers to that amount of an translation elongation inhibitor, such as for example SVC 112, that is sufficient to effect a certain action, such as treatment, as defined below, when administered to a mammal in need of such treatment; modulating the catalytic activity of the ribosome, such as when administered to an environment where modulation of the catalytic activity of a ribosome is desired; or disrupting the function of a ribosome, such as when administered to an environment where disrupting the function of a ribosome is desired. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound or co-compounds, the dosing regimen to befollowed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.

[0057] The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.

[0058] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0059] The term “subject” refers to an animal, such as a mammal, for example a human that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human. As used herein, the term “patient” includes a subject that may have, or be at risk of cancer, or a subject that may or may not respond to treatment by an transcription elongation factor such as SVC 112.

[0060] As used herein “cancer” refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named after the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemia, lymphoma and myeloma. Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one.

[0061] Administration of SCV112 may be administered by any method that enables delivery of the inhibitors to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. The SCV112 may be administered sequentially, concurrently or simultaneously with another therapeutic agent, such as an oncology therapeutic.The term “sequential” or “sequentially” refers to the administration of each therapeutic agent of the combination therapy either alone or in a medicament, one after the other, wherein each therapeutic agent can be administered in any order. Sequential administration may be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and / or the agents are administered according to different dosing schedules, for example, one agent is administered daily, and the second agent is administered less frequently such as weekly. The term “concurrently” refers to the administration of each therapeutic agent in the combination therapy of the disclosure, either alone or in separate medicaments, wherein the second therapeutic agent is administered immediately after the first therapeutic agent, but that the therapeutic agents can be administered in any order. The term “simultaneous” refers to the administration of each therapeutic agent of the combination therapy of the disclosure in the same medicament.

[0062] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound, for example SCV112, calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

[0063] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, theseexamples in no way limit the dose and administration regimen that may be provided to a subject in practicing the present disclosure.

[0064] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0065] The amount of SCV112 administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg / day, preferably about 0. 7 to about 2500 mg / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day. In one preferred embodiment, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. In some cases, the aforesaid dosage examples may describe a dosage range fora combination of SCV112 and another oncology therapeutic. Tn alternative embodiments, the aforesaid dosage examples may describe dosage ranges for SCV112 individually.

[0066] Suitable pharmaceutical carriers include inert diluents or fdlers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Nonlimiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0067] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

[0068] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

[0069] Pharmaceutical compositions suitable for the delivery of SCV112 as described herein, and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.In certain examples, SCV112 may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

[0070] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0071] In additional examples, SCV112 may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001 ), the disclosure of which is incorporated herein by reference in its entirety.

[0072] For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrants will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

[0073] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about O wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

[0074] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated. The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety. Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations are described in U.S. PatentNo. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology Online, 25(2), 1-14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00 / 35298. The disclosures of these references are incorporated herein by reference in their entireties.

[0075] In additional examples, SCV112 may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

[0076] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of the disclosure used in the preparation of parenteral solutions may be increased using appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus, compounds of the disclosure may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

[0077] The translation elongation inhibitors of the disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. The disclosures of these references are incorporated herein by reference in their entireties. Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0078] In additional examples, SCV112 can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurizedcontainer, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant known within the art. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

[0079] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the disclosure comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0080] Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of SVC112, a suitable powder base such as lactose or starch and a performance modifier such as I-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0081] A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to lOOOmg of SVC 112 per actuation and the actuation volume may vary from 1 pL to 1 OOpL. A typical formulation includes SVC112, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the disclosure intended for inhaled / intranasal administration.

[0082] Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0083] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the disclosure are typicallyarranged to administer a metered dose or “puff’ containing, preferably, a desired amount of SVC112. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

[0084] SVC112 and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and noninclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO91 / 11172, WO94 / 02518 and WO98 / 55148, the disclosures of which are incorporated herein by reference in their entireties.

[0085] Inasmuch as it may be desirable to administer SVC112, for example, for the purpose of treating a particular disease or condition such as cancer, it is within the scope of the present disclosure that a first pharmaceutical composition containing SVC112, and in some embodiments optionally a second pharmaceutical composition containing a second oncology therapeutic, may conveniently be combined in the form of a kit suitable for administration and / or co-admini strati on of the compositions. Thus, the kit of the disclosure includes one or more separate pharmaceutical compositions, one of which contains SVC112 and in certain embodiments, another of which contains a second, or even third or more oncology therapeutics, and means for singly or separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the disclosure is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid.

[0086] In some aspects, the SVC 112 are part of a combination therapy. As used herein, the term “combination therapy” refers to the administration of a SVC112, optionally together with one or more additional oncology therapeutic or cancer treatment, either sequentially, concurrently or simultaneously. The therapeutic effectiveness of the combinations of the disclosure in certain tumors may be enhanced by combination with other approved or experimental cancer therapies,such as radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents.

[0087] When a combination therapy comprising an additional anti-cancer agent is used, the one or more additional oncology therapeutics may be administered sequentially, concurrently or simultaneously with SVC 112 and / or the oncology therapeutic. In one embodiment, the additional oncology therapeutics is administered to a mammal (e.g., a human) prior to administration of SVC 112. In another embodiment, the additional oncology therapeutic is administered to the mammal after administration of SVC 112. In another embodiment, the additional oncology therapeutic is administered to the mammal (i.e., a human) simultaneously with the administration of the SVC112 and / or oncology therapeutic of the disclosure.

[0088] The disclosure also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a SVC112. Unless indicated otherwise, all references herein SCV112 or other oncology therapeutic include references to salts, solvates, hydrates, analogs, and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.

[0089] SVC112 may exist in the form of pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the parent compound. The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds described herein.

[0090] The disclosure also relates to prodrugs of the compounds of the formulae provided herein. Thus, certain derivatives of compounds of the disclosure which may have little, or no pharmacological activity themselves can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.

[0091] Prodrugs in accordance with the disclosure can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known tothose skilled in the art as 'pro-moieties' as described, for example, in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0092] This present disclosure provides methods and materials involved in assessing biological samples for the status of biomarkers indicative of cancer patient response to anti-cancer therapeutic regimens. In general, an analysis of the biomarkers can reveal whether a cancer cell is likely sensitive or resistant to treatment with certain anti-cancer compounds, namely transcription elongation factors such as SVC112. Thus, the present disclosure is generally related to the identification of cancer patients that are predicted to benefit from the therapeutic administration of SVC112.

[0093] As used herein, a biological marker (“biomarker” or “marker”) is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological responses to therapeutic interventions, consistent with NIH Biomarker Definitions Working Group (1998). Markers can be individual genes, or genome-wide markers, or individual residues of a protein, such as a histone residue that may be chemically modified, such as through acetylation and deacetylation. Markers can also include patterns or ensembles of characteristics indicative of particular biological processes. Markers can also include patterns or ensembles of characteristics indicative of dose-dependent biological processes. The biomarker measurement can increase or decrease (“modulate”) to indicate a particular biological event or process. In addition, if the biomarker measurement typically changes in the absence of a particular biological process, a constant measurement can indicate occurrence of that process.

[0094] There are three distinct types of cancer biomarkers: (1) prognostic biomarkers, (2) predictive biomarkers, and (3) pharmacodynamic biomarkers. A prognostic biomarker is used to classify a cancer, e g., a solid tumor, according to aggressiveness, i.e., rate of growth and / or metastasis, and refractiveness to treatment. This is sometimes called distinguishing “good outcome” tumors from “poor outcome” tumors. A predictive biomarker is used to assess the probability that a particular patient will benefit from treatment with a particular drug. A pharmacodynamic biomarker is an indication of the effect(s) of a drug on its molecular target while the patient is taking the drug. Accordingly, pharmacodynamic biomarkers often are used to guide dosage level and dosing frequency, during the early stages of clinical development of a new drug.In another embodiment, the present disclosure includes a method for determining the sensitivity or resistance of a cancer subject to treatment with an translation elongation inhibitor. In this example, SVC112. In one example, the method includes obtaining a biological sample from the subject, and preferably a subject having a cancer selected from: acute myeloid leukemia (AML), or colorectal cancer (CRC), and measuring the level of one or more biomarkers in a biological sample obtained from a subject, wherein the one or more biomarkers is selected from: MCL-1, BCL-XL, and c-Myc.

[0095] Additional embodiments of the disclosure include a diagnostic kit for determining the sensitivity or resistance of a cancer patient, and preferably a patient suffering from acute myeloid leukemia (AML) or colorectal cancer (CRC) to treatment with a translation elongation inhibitor. In a preferred example, the kit of the disclosures includes reagents for detecting and quantifying one or more biomarkers selected from MCL-1, BCL-XL, and c-Myc levels in a biological sample, and instructions for interpreting the results to determine whether the patient is sensitive or resistant to translation elongation inhibitor based on the biomarker level.

[0096] In one embodiment, the kit includes reagents for detecting and quantifying the expression level, activity, or presence in a biological sample of one or more biomarkers level of the biomarker selected from MCL-1, BCL-XL, and c-Myc. In another embodiment, the kit includes reagents for detecting and quantifying the phosphorylation level of c-Myc at position Ser62. In certain embodiments, the reagents for detecting and quantifying one or more biomarkers include reagents for detecting and quantifying one or more biomarkers using an assay selected from the group consisting of enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), western blotting, quantitative polymerase chain reaction (qPCR), western blot, or RNA sequencing.

[0097] The term “biological sample” encompasses a clinical sample, but also, in some instances, includes cells in culture, cell supernatants, cell lysates, blood, serum, plasma, urine, cerebral spinal fluid, biological fluid, tissue samples, tumor tissue, or a biopsy sample. The sample may be pretreated as necessary by dilution in an appropriate buffer solution or concentrated, if desired. In embodiments, the biological sample is a blood sample. The level of biomarker can be measured in the biological sample using any method known to those of ordinary skill in the art, and can include an assay selected from the group consisting of enzyme-linked immunosorbent assay (ELISA),western blotting, immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR), western blot, or RNA sequencing.

[0098] In another embodiment, the present disclosure includes method of treating cancer in a subject including administering to the subject a therapeutically effective amount of a translation elongation inhibitor, such as SVC112 based on the level of at least one biomarker in a biological sample from the subject, wherein the biomarkers are selected from MCL-1, BCL-XL and c-Myc, wherein the level of the measurement of the biomarker when compared to a predetermined threshold indicates whether the subject will be sensitive (responder) or resistant (non-responder) to treatment by a translation elongation inhibitor, such as SVC112.

[0099] A subject can be determined to be sensitive to treatment with an translation elongation inhibitor, such as SVC112, where: the level of MCL-1 is above a predetermined threshold; the level of BCL-XL is below a predetermined threshold; or the level of phosphorylation of c-Myc at Ser62 is below a predetermined threshold. Conversely, a subject can be determined to be resistant to treatment with an translation elongation inhibitor, such as SVC112, where: the level of MCL-1 is below a predetermined threshold; the level of BCL-XL is above a predetermined threshold; or the level of phosphorylation of c-Myc at Ser62 is above a predetermined threshold. Next, a therapeutically effective amount of a translation elongation inhibitor, such as SVC112 can be administered to a subject determined to be sensitive based on the level of the at least one of the aforementioned biomarkers.

[0100] In certain embodiments, the predetermined threshold of one or more of the biomarkers is determined based on a control population of cancer patients, preferably having the same type of cancer as the subject, who have responded to translation elongation inhibitor treatment, and preferably SVC112. In certain other embodiments, the predetermined threshold of one or more of the biomarkers is determined based on a control population of cancer patients, preferably having the same type of cancer as the subject, who have not responded to translation elongation inhibitor treatment, and preferably SVC 112. As determination of responsive and non-responsive subjects can be made in vitro, or in vivo.

[0101] Additional embodiments of the disclosure include methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a translation elongation inhibitor, such as SVC 112m based on the level of at least one biomarker in a biological sample from the subject, wherein the biomarkers are selected from MCL-1, BCL-XLand c-Myc. In this embodiment, preferably human patient is sensitive to with the translation elongation inhibitor treatment, and preferably SVC112 when one or more of the following is measured: the level of MCL-1 is above a predetermined threshold, the level of BCL-XL is below a predetermined threshold; or the level of phosphorylation of c-Myc at position Ser 62 is below a predetermined threshold. In additional embodiment, a second oncology therapeutic can be administered to the subject, which can be selected from a BCL-2 inhibitor, a BCL-XL inhibitor, and an ERK inhibitor. In a preferred embodiment, the BCL-2 inhibitor is venetoclax, while the ERK inhibitor is ulixertinib.

[0102] As used herein, “predetermined threshold (value)” means the threshold numeric value at which a classifier gives the desirable balance between (the cost of) false negatives and false positives. Preferably, “predetermined threshold (value)” means the potential threshold numeric value to divide the entire population (of patients or subjects) into two (or more) subgroups so that it can bring clinical benefit to patients with the threshold or a certain level of gene expression, activity, or secondary modification, such as phosphorylation, compared to patients with the differential (level of gene expression, activity, or secondary modification, such as phosphorylation than the threshold (sometimes referred to using designations as “low” or “high” relative to the threshold.

[0103] In case a threshold value is, preferably, “predetermined threshold (value)” means the potential threshold numeric value to divide the entire population (of patients or subjects) into two (or more) subgroups so that it can bring clinical benefit to patients with the threshold or lower biomarker level.

[0104] In one example a predetermined threshold (value) can include a high level subgroup, wherein the level of MCL-1 is above a predetermined threshold meaning that patient is likely sensitive to treatment by SVC 112. In another example a predetermined threshold (value) can include a low level subgroup, wherein the level of MCL-1 is below a predetermined threshold meaning that patient is likely resistant to treatment by SVC 112.

[0105] In another example a predetermined threshold (value) can include a low level subgroup, wherein the level of BCL-XL is below a predetermined threshold meaning that patient is likely sensitive to treatment by SVC 112. In another example a predetermined threshold (value) can include a high level subgroup, wherein the level of MCL-1 is above a predetermined threshold meaning that patient is likely resistant to treatment by SVC 112.In another example a predetermined threshold (value) can include a low level subgroup, wherein the level of phosphorylation of c-Myc at positions Ser62 is below a predetermined threshold meaning that patient is likely sensitive to treatment by SVC112. In another example a predetermined threshold (value) can include a high level subgroup, wherein the level of phosphorylation of c-Myc at positions Ser62 is above a predetermined threshold meaning that patient is likely resistant to treatment by SVC 112.

[0106] In some embodiments, “predetermined threshold” is statistically (and clinically) determined, refined, adjusted and / or confirmed through, on, or based on, a clinical study and analyses of outcome thereof (collectively, “clinical data”), and / or a preclinical or non-clinical study (collectively, “non-clinical data”), in order to minimize undesirable effects of false positives and false negatives. In some embodiments, “predetermined threshold” is statistically (and clinically) determined, refined, adjusted and / or confirmed on, or based on, clinical data (and optionally non-clinical data), further more preferably randomized clinical data (and optionally non-clinical data), to ensure all patients that benefit from treatment are included in the high or low subgroup.

[0107] More preferably, “predetermined threshold” is determined, refined, adjusted and / or confirmed through, on, or based on pharmacological characteristics (i.e., mechanism of action), preclinical or non-clinical study data, clinical study data, and commercial sample data purchased from external companies or the like, in order to maximize clinical benefit from “high” subgroups compared with “low” subgroup as described above. Some statistical method such as Adaptive Biomarker Threshold Design (i.e., maximum likelihood approach), Jiang W, Freidlin B, Simon R. Biomarker-Adaptive Threshold Design: A Procedure for Evaluating Treatment With Possible Biomarker-Defined Subset Effect, J Natl Cancer Inst. 2007; 99(13): 1036-43, and the like is used to determine, refine, adjust and / or confirm the threshold using the all available data of pre / non-clinical studies, clinical studies, commercial sample, etc. (to ensure all patients that benefit from treatment are included in the high and low subgroup for the biomarkers selected from: MCL-1, BCL-XL, and c-Myc.

[0108] In some preferred embodiments, when a group of patients suffering from a cancer are treated by administering a translation elongation inhibitor, such as SVC 112 or placebo with or without a further medicament, and said group is divided into a “high” subgroup and “low” subgroup for the biomarkers described herein using the predetermined threshold, average anti-cancer efficacy of the administered translation elongation inhibitor, such as SVC112 inhibitor is better than that of control (e.g. placebo) with clinical(ly) (meaningful) benefit in the “high” or “low” subgroup (depending on the biomarker), while average anti-cancer efficacy of the administered a translation elongation inhibitor, such as SVC112 is slightly better or not better than that of control (e.g. placebo) with no clinical(ly) (meaningful) benefit in the “high” or “low” subgroup (depending on the biomarker). In more preferred embodiments, average anti-cancer efficacy of the administered translation elongation inhibitor, such as SVC112 is statistically significantly better than that of control (e.g. placebo) with clinical(ly) (meaningful) benefit in one subgroup, while average anti-cancer efficacy of the administered HER3 inhibitor is not statistically significantly better than that of control (e.g. placebo) with no clinically) (meaningful) benefit in the other subgroup.

[0109] In other preferred embodiments, when a group of patients suffering from a cancer is divided into a “high” subgroup and a “low” subgroup depending on the biomarker to be evaluated using the predetermined threshold, and each group is treated by administering a translation elongation inhibitor, such as SVC112 or placebo with or without a further medicament, average anti-cancer efficacy of the administered SVC 112 is better than that of a control (e.g. placebo) with clinical(ly) (meaningful) benefit in the “high MCL-1” subgroup, the “low BCL-XL subgroup”, or the “low phosphorylation at Ser62 subgroup,” while average anti-cancer efficacy of the administered SVC112 is slightly better or not better than that of control (e.g. placebo) with no clinical(ly) (meaningful) benefit in the “low MCL-1” subgroup, the “high BCL-XL subgroup”, or the “high phosphorylation at Ser62 subgroup.”

[0110] In more preferred embodiments, average anti -cancer efficacy of the administered SVC 112 is statistically significantly better than that of control (e.g. placebo) with clinical(ly) (meaningful) benefit in the “high MCL-1” subgroup, the “low BCL-XL subgroup”, or the “low phosphorylation at Ser62 subgroup,” while average anti-cancer efficacy of the administered SVC 112 is not statistically significantly better than that of control (e.g. placebo) with no clinical(ly) (meaningful) benefit in the low MCL-1” subgroup, the “high BCL-XL subgroup”, or the “high phosphorylation at Ser62 subgroup.”

[0111] In other preferred embodiments, when a group of patients suffering from a cancer is divided into a “high” subgroup and “low” subgroup for one or more of MCL-1, BCL-XL, and c-Myc usingthe predetermined threshold, and the sensitive subgroup is treated by administering a SVC112 and the resistant subgroup is treated by administering a different, or no therapy.

[0112] In other preferred embodiments, when “high MCL-1” subgroup, the “low BCL-XL subgroup”, or the “low phosphorylation at Ser62 subgroup,” patients suffering from a cancer, and in particular AML or colorectal cancer, are identified using the predetermined threshold, and the patients are treated by administering a translation elongation inhibitor, such as SVC112m the inhibitor being statistically significantly better than that of control (e.g. placebo) with clinical(ly) (meaningful) benefit.

[0113] As used herein, “BCL-2 inhibitor” refers to any molecule that partially or fully inhibits the activity of BCL-2. As used herein, “BCL-XL inhibitor” refers to any molecule that partially or fully inhibits the activity of BCL-XL. As used herein, “ERK inhibitor” refers to any molecule that partially or fully inhibits the activity of ERK or the ERK pathway.

[0114] All publications, patents and patent applications cited herein are hereby incorporated by reference in their entireties.

[0115] The methods and compositions of the disclosure now being generally described will be more readily understood by reference to the following examples, which are included merely for the purposes of illustration of certain aspects of the embodiments of the present disclosure. The examples are not intended to limit the disclosure, as one of skill in the art would recognize from the above teachings and the following examples that other techniques and methods can satisfy the claims and can be employed without departing from the scope of the disclosure. Indeed, while this disclosure has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the disclosure encompassed by the appended claims.

[0116] EXAMPLES

[0117] Example 1 : Overview and Experimental Rationale.

[0118] As described herein, cancer cells, from distinct cancer indications, exhibit a broad range of sensitivities to SVC 112, an inhibitor of translation elongation with a first-in-class MoA: preventing the dissociation of eEF2 from the ribosome. In AML and Myeloma cells, sensitivity to SVC 112 appears dependent upon the relative protein levels of the BCL-2 family members BCL-XL and MCL-1. Treatment of sensitive cells induces robust apoptosis in culture and produces robust tumorgrowth control and prolonged survival in xenograft models. Tn CRC cells, resistance to SVC112 appears dependent, in part, upon phosphorylation and stabilization of c-Myc. Pharmacological inhibition of ERK1 / 2 in combination with SVC 112 induces c-Myc depletion, synergizes to inhibit CRC growth in culture, and producing tumor growth control in xenograft models.

[0119] Importantly, inhibition of translation elongation by SVC 112 does not broadly induce apoptosis in cancer or normal cells. For example, SVC112 depletes c-Myc and MCL-1 in both MV-4-11 andKasumi-3 AML cells but only the former undergoes apoptosis. InKasumi-3, another related pro-survival protein BCL-XL is expressed to a higher level than in MV- 4-11, suggesting that the presence of this second, more stable pro-survival factor protects the former. The inverse correlation between MCL-1 and BCL-XL protein levels and SVC112 sensitivity in AML cells supports the important of these anti-apoptotic proteins as biomarkers for SVC112 sensitivity. In addition, protein depletion by SVC112 in PBMCs, which are readily accessible from peripheral blood draws, may be the basis for pharmacodynamics biomarkers to monitor SVC112 effect in vivo.

[0120] Additionally, the broad spectrum of SVC 112 ICso in CRC cells suggests other mechanisms underlying sensitivity / resistance for these cells, beyond differential c-Myc stability. For example, preliminary data shows that the translation inhibition induced by SVC112 is roughly inversely proportional to ICso, with low ICso correlating with robust inhibition and high ICso correlating with partial inhibition. Given high conservation of the protein synthesis machinery between cells, it is unlikely that it is the result of differential ribosome / eEF2 and SVC 112 interaction, but rather other well know factors such as drug efflux. Moreover, differential cellular fate in response to SVC 112 and HHT treatment are therapeutically relevant. Both are translation elongation inhibitors (with distinct MOA's), both inhibit in vitro translation elongation from a standardized template, both equivalently induce depletion of the studied short half-life proteins (MCL-1 and c-Myc) in PBMC cells, but only HHT induces robust markers of apoptosis. These data confirm prior observations that HHT does not discriminate between cancer and normal cells from patient matched HNSCC samples, while SVC112 preferentially inhibits cancer cell growth from the same samples. Cumulatively these data suggest that distinct mechanisms of translation elongation inhibition may induce disparate cellular responses.

[0121] With that in mind, the current understanding of translation remains primarily focused on translation initiation, with the elongation steps being generally regarded as an unregulatedprocessive afterthought. Yet, a large body of literature show that elongation is highly regulated by mechanisms such as ribosome pausing and that dysregulation occurs during aging, neurodegeneration and cancer. Furthermore, inhibitors of elongation can be mRNA-specific as seen with the PF-06446846 family of drugs that modulate cholesterol homeostasis. PF- 06446846 engages the nascent peptide in a sequence-specific manner at the ribosome exit tunnel to inhibit translation elongation. It shows remarkable selectivity by inhibiting elongation around codon 34 of the PCSK9 transcript and affecting less than 0.5% of transcripts in ribosome profiling assays 33. Likewise, even ‘general’ protein synthesis inhibitors are recognized to exhibit inhibitor-specific effects upon closer study. For example, recent work has demonstrated that the non-clinically relevant elongation inhibitors cycloheximide, puromycin, and anisomycin preferentially affect distinct mRNA subsets resulting in differential cellular protein levels in a cell-type and inhibitorspecific manner. For SVC112, Applicants have previously reported mRNA selectivity by RiboSeq in HNSCC cells, where mRNAs for inflammatory response and p53 pathways were preferentially associated with the ribosome when SVC112 was present. These data and the findings further support the idea that not all inhibitors of translation elongation behave similarly in terms of the mRNA's targeted or cellular fate in response to their treatment.

[0122] Finally, Applicants note that HHT, SVC112 and S63845 show a decreasing breadth of activity amongst the matched panel of ten cell lines tested here. Applicants suggest that while HHT has broad efficacy, it is accompanied by broad toxicity due to apoptotic induction in PBMC’s (Fig.

[0123] 5C) and failure to discriminate between HNSCC and normal cells, all of which agree with its noted clinical toxicity (FDA drug label 2035851b!). At the other end of the spectrum, highly specific agents like S63845 may show limited efficaciousness, only under very specific circumstances. In contrast, SVC112 exhibits efficacy in animal xenograft models without accompanying loss of body weight, a common surrogate measure of toxicity (Fig. 3B', C”, D” and supplemental Fig. 1A”). This suggests SVC 112 represents an optimal balance of safety and efficacy.

[0124] Example 2: SVC112 shows a wide range of growth inhibition in different cancer cell lines.

[0125] Applicants assessed the effect of SVC 112 on 40 cancer cell lines representing Acute Myeloid Leukemia (AML), Multiple Myeloma (Myeloma), Colorectal Cancer (CRC), and Head and Neck Squamous Cell Carcinoma (HNSCC) using 72 hr growth assays and found that IC50 values varied widely among the cell lines (6 nM to >10 LIM; Fig. 1A). To investigate the consequences of SVC112 exposure Applicants analyzed effects to global de novo protein synthesisas measured by amino acid analog incorporation, and then monitored for changes to specific proteins by Western blot. For these experiments 1 pM of SVC 112 was used as it represents achievable drug plasma concentration in mice; with 6hr of 1 pM SVC112 mimicking plasma exposure following a single dose of SVC112 in xenograft experiments where Applicants observed significant tumor growth inhibition. After 2hr of incubation with 1 pM of SVC112, near complete loss of new protein synthesis was observed in 4 acutely sensitive cell lines representing the studied cancer indications (Fig. IB), in agreement SVC112’s known mechanism of action.

[0126] Inhibition of synthesis is expected to result in the depletion of proteins with short halflives. Correspondingly, after 6 or 24 hr of 1 pM SVC112 incubation near complete depletion of MCL-1 and c-Myc is observed (Fig. 2A). MCL-1 is an anti-apoptotic member of the Bcl-2 family, which primarily functions to antagonize the apoptotic effector proteins BAX and BAK; and as such depletion of MCL-1 may predispose cells to apoptosis. AML and myeloma cells treated with SVC112 exhibit apoptotic induction as detected by PARP cleavage (* in Fig. 2A). In contrast, the two solid tumor lines show little PARP cleavage despite the loss of MCL-1 after 6 or 24 hr of continuous drug incubation. Annexin V staining for phosphatidyl serine (PS) presentation and Propidium Iodide (PI) uptake confirmed robust apoptosis in AML and myeloma cells (representative primary data shown in Fig. 2B, quantifications in Fig. 2B'); and the lack thereof in solid tumor cell lines even with prolonged recovery times after 6 hr of drug treatment to capture delayed apoptotic responses (‘6-18 hr’ and ‘6-42 hr’ samples). Collectively, these data suggest that SVC112 inhibits new protein synthesis and cell growth, but SVC112 mediated translation suppression alone is not sufficient to induce apoptosis in all SVC 112 sensitive cell lines.

[0127] To address the reversibility of SVC 112 effects, Applicants exposed cells to 1 pM SVC 112 for 6 hr, washed the drug out, and analyzed protein levels after 18 hr of recovery (‘6-18hr’ lanes in Fig. 2B), totaling a 24 hr time course. When compared to cells treated continuously for 24 hr (’24 hr’ lanes), the levels of MCL-1 and c-Myc recovered in most cell lines suggesting that effects of transient SVC112 exposure are reversable. The exceptions being AML-EOL-1 and MV-4-11 cells that show no recovery of MCL-1 or c-Myc, complete PARP cleavage, and near complete loss of the Nucleolin loading control regardless of transient or continuous SVC112 exposure. These observations combined with the PS / PI co-staining shown in Fig 2B / B' suggest that AML-EOL-1 and MV-4-11 cells fail to recover following washout due to rapid induction of apoptosis after transient SVC112 exposure.Example 3: Anti-apoptotic protein levels correlate with sensitivity to SVC112,

[0128] Given the apparent importance of apoptosis in how cells respond to SVC112, Applicants examined basal (no drug) levels of pro- (red) and anti-(cyan) apoptotic proteins in eight AML cell lines representative of sensitive (green), moderately sensitive (yellow) or resistant (orange) groups shown in Fig. 1 A. Of the two pro-apoptotic proteins assessed, BAX levels are highest in the three most sensitive cell lines, while BAK levels are uniform across the cell lines with no apparent correlation to sensitivity (Figure 2C). Of the three anti-apoptotic proteins assessed, MCL-1 levels are higher in more sensitive lines, BCL-XL levels are higher in the two most resistant lines, while BCL-2 levels vary across the cell lines with no apparent correlation to sensitivity. Densitometric quantification of protein levels and assessment with Pearson correlation coefficient (p) show that higher MCL-1 levels strongly correlate with low SVC112 IC50 ( =-0.8013, Fig. 20) while high BCL-XL levels strongly correlate with high SVC112 IC50 ( =0.8457, Fig. 2C”). Collectively these results suggest that SVC112 sensitive lines may rely upon MCL-1 for survival, while resistant cells may rely on BCL-XL. In contrast to the short-lived MCL-1 protein, BCL-XL has a half-life of ~20 hr and is expected to persist during SVC 112 inhibition of protein synthesis. Therefore, cells with high basal level of BCL-XL can be resistant to apoptosis induction by SVC112. To test this hypothesis, Applicants treated Kasumi-3 cells that exhibit relatively low levels of MCL-1 and relatively high levels of BCL-XL with SVC112. Under the same conditions that induce robust apoptosis in AML-EOL-1, MV-4-11 and OCLAML-3 cells (Fig. 2A), Kasumi-3 cells show little sign of PARP cleavage despite loss of the unstable proteins MCL-1 and c-Myc, regardless of SVC112 exposure periods (6 vs 24hr), and exhibit complete recovery of MCL-1 and c-Myc following transient SVC112 exposure (Fig. 2D). These results further support the idea that SVC112-mediated inhibition of new protein synthesis alone is not sufficient to induce apoptosis.

[0129] Example 4: Apoptosis induction in cell lines accompanies survival benefit in mouse xenograft models.

[0130] To address the efficacy of SVC 112 at inhibiting cell growth in vivo Applicants next performed mouse xenograft studies. AML-EOL-1, MV-4-11 and HCT116 were assessed because while they are among the most sensitive cell lines in vitro (Fig. 1A), they undergo apoptosis to vastly different levels in response to SVC 112 (Fig. 2A-B). For comparative purposes traditional flank xenograft implantation was utilized for all cell lines (Figure 3A, C, D and 6A), with additional orthotopic implantation performed for one AML cell line to assess effects in a morerelevant physiological compartment (Figure 3B). Regardless of implantation site, drug formulation or route of drug delivery, SVC 112 shows significant tumor growth control in all three models (Fig.

[0131] 3 A, C, D, and 6A). Furthermore, SVC112 provided significant survival benefit in mice bearing MV-4-11 and AML-EOL-1 xenografts (Fig. 3B, C’, and 6A1). In contrast, HCT116 tumors regrew after cessation of drug treatment resulting in no significant survival benefit (Fig. 3D’). Given that SVC 112 induces apoptosis in AML-EOL-1 and MV-4-11 cells but not in HCT116 cells (Fig.

[0132] 2A-B), loss of xenografted tumor cells to cell death could explain the survival benefit in AML-EOL-1 and MV-4-11, and the lack thereof in HCT116 xenografts. Importantly, for all xenograft experiments animals appeared to tolerate SVC 112 treatment, with no significant changes in body weight observed relative to controls (Fig. 3B', C”, D”, and 6A”).

[0133] Example 5: c-Myc persists in SVC112-resistant CRC cells.

[0134] CRC cell lines show abroad range of SVC112 sensitivity with in vitro growth assays (Fig.

[0135] 1A). Study of two representative resistant CRC cell lines (DLD-1 and SW948) identified one clear difference from sensitive HCT116 cells; depletion of c-Myc in response to SVC112 treatment. Under conditions where c-Myc is depleted in HCT116 cells (1 pM for 6 hr; Fig. 2A), it persists in DLD-1 and SW948 cells (Fig. 4A, SVC112 lane). In contrast, the unstable proteins Cyclin DI and MCL-1 are depleted to near completion in all three cell lines, suggesting that SVC112 is functioning to inhibit protein synthesis. Stability of c-Myc is regulated in part by phosphorylation at Ser62, which is primarily mediated by hyperactive ERK / MAPK signaling in CRC. Treatment with Ulixertinib, a small molecule ERK1 / 2 inhibitor currently being assessed in numerous phase 2 clinical trials (e.g., NCT05221320, NCT03417739, NCT03698994), led to a partial reduction of Myc as reported previously (Fig. 4A, Ulixertinib lane). Interestingly, co-treatment of SVC 112 and Ulixertinib led to near complete depletion of total and Ser62 phosphorylated c-Myc in these highly SVC112 resistant cell lines. One possible explanation for this combinatorial effect is that phosphorylation by ERK1 / 2 helps stabilize Myc, and reduction of this renders Myc sensitive to depletion during SVC 112 mediated translation inhibition.

[0136] To ask whether the addition of Ulixertinib can generally enhance the growth inhibitory effect of SVC112, Applicants tested the effect of SVC112 / Ulixertinib combinations on nine CRC cell line exhibiting a range of sensitivities to SVC112; with cells treated with a 10-dose drug range (0 to 10 pM) in pairwise combinations and growth assessed after 72 hr. Combination index was calculated using the Chou and Talalay method to identify synergistic (<1), additive (~1) andantagonistic (>1) interactions. Additive and synergistic effects were observed in all cell lines and for nearly all growth fractions affected (Fig 4B). Overall synergy (lower CI values) was more robust in SVC112 resistant cell lines (note ICso values), with could be explained by robust SVC112 single agent activity in sensitive cells leaving limited capacity for synergistic effect with Ulixertinib. The CI synergy observed in SVC112 resistant DLD-1 cells was replicated in 10-day clonogenic assays where cells were exposed to drugs for the first 24 hr of growth (representative primary data shown in Fig. 4C, quantifications in Fig. 40, dashed lines represent expected additive effects).

[0137] To investigate whether in vitro synergy between SVC112 and Ulixertinib translates to in vivo tumor growth control, Applicants next performed mouse xenograft studies. In flank tumors from the SVC112-resistant DLD-1 cell line, combination of SVC112 and Ulixertinib reduced tumor growth significantly compared to vehicle controls, whereas the single drug treatments had no significant effects (Fig. 4D). As in the case of HCT116 xenografts, however, tumors resumed growth after cessation of treatment and survival benefit was limited and not significant (Fig. 4D').

[0138] Example 6: Comparison of SVC112 to related current and future oncology drugs.

[0139] MCL-1 is a cancer driver in AML and Myeloma, and accordingly several MCL-1 inhibitors are under development as therapies for these indications. HHT, an inhibitor of translation elongation that is approved for CML patients, is being assessed in clinical trials for hematologic cancers because of the potential to deplete short-lived proteins including MCL-1 (e.g., NCT03564873, NCT04874194). SVC112 is also an inhibitor of translation elongation that can deplete MCL-1, albeit with a different mechanism. HHT binds the ribosome A site interfering with positioning of aminoacyl-tRNAs, whereas SVC112 prevents the dissociation of the accessory factor eEF2 from the ribosome. Applicants therefore compared the relative activities of SVC 112, HHT and the MCL-1 inhibitor S63845, all clinically relevant agents that target similar molecular processes or molecular targets.

[0140] HHT and SVC 112 show similar potency for the inhibition of translation elongation with cell extracts in vitro (Fig. 5 A), but vastly different growth inhibitory profiles in AML and myeloma cell lines in culture (Fig. 5B). Specifically, HHT shows universal nM ICsoin the 10 cell lines tested, while SVC112 shows a wide range of ICso (Fig. 5B). The ability of SVC112 but not HHT to discriminate among different cell lines is in agreement with prior data showing that HTT exhibits similar growth inhibition between cancer and normal cells from the same HNSCC patients,whereas SVC112 shows greater efficacy on cancer relative to normal cells of the same patient-matched pairs. Differential effects of HHT and SVC112 on cancer cells extends to Peripheral Blood Mononuclear Cells (PBMC), representing normal cells of the hematologic compartment. Both SVC 112 and HHT treatment led to depletion of MCL-1 and c-Myc, but only HHT induced the surrogate apoptosis markers of PARP and Caspase 3 cleavage to appreciable levels (Fig. 5C). Even with prolonged incubation times (1 pM for 24 hr) SVC112 induced only partial (-20%) PARP cleavage and de minimis levels of Caspase 3 cleavage relative to HHT. Importantly, 6 hrs of 0.1 and 1 pM HHT incubation, which resulted in robust PARP and Caspase 3 cleavage, mimics plasma concentrations observed in patients.

[0141] In contrast, SVC 112 and the MCL-1 inhibitor S63845 showed the opposite relationship. Five of the ten cell lines are similarly sensitive to both drugs (low ICso), one is moderately sensitive to both, and one (Kasumi-3) is resistant to both. The resistance of Kasumi-3 to direct MCL-1 inhibition supports the idea that these cells do not rely on MCL-1 for survival as suggested in Fig.

[0142] 2D. In the three remaining cell lines, SVC112 is significantly more potent than S63845, possibly because SVC112 affects more proteins than just MCL-1 (e.g. c-Myc).

[0143] Example 7: Materials & Methods.

[0144] Cell growth assays and drug treatment: Cell lines were authenticated by DNA fingerprinting (STR profile) before and during use at ATCC and the University of Colorado Cancer Center Cell Technologies Shared Resource core. ICso for cell growth and CI were determined as Applicants have previously describedin the art. (See Ref. No. 9 & 11) In brief, cells were seeded at 4000 cells per well in 96-well plates, grown overnight, and treated with a 10-dose drug range (0, 0.001, 0.01, 0.06, 0.3, 0.6, 1, 3, 6, 10 pM final) of SVC112, HHT, S63845 and / or Ulixertinib for 72 hr. Cell viability was determined by CellTiter-Glo Luminescent Cell Viability Assay (Promega G7570) following manufacturer’s instructions, with luminescence measured by plate reader (Synergy 2, BioTek). ICso was calculated using nonlinear regression in Prism (GraphPad Software). CI was calculated using the Chou and Talalay method in CalcuSyn (BioSoft). Clonogenic assays were performed as previously described in the art. (See Ref. No. 9 & 11) In brief, DLD-1 cells were seeded at 200 cells per well in 6-well plates, grown overnight, treated with the indicated drug concentrations for 24 hr, followed by drug washout, followed by 9 days of growth in fresh media. Colonies were fixed with trichloroacetic acid (Sigma-Aldrich T6399), stained with Sulforhodamine B (Sigma- Aldrich SI 402), and manually counted. Digital images were acquiredusing a stereo microscope (SZX12, Olympus Imaging Inc.) and digital camera (SPOT Insight 2.0, Diagnostic Instruments Inc.). All drugs were solubilized in DMSO. SVC112 was provided by SuviCa Inc. (Boulder, CO USA). Homoharringtonine, S63845, and Ulixertinib were purchased from MedChemExpress USA (HY-14944, HY-100741, HY-15816).

[0145] Western Blots: Protein extraction and Western blots were performed as previously described (See Ref. No. 9 & 11). For SVC112 washout, cells were treated for the indicated drug concentrations and times, washed 3 times in IX PBS, and then allowed to recover in fresh media without drug for the indicated periods. Protein extracts were prepared in RIPA buffer, quantified via BCA protein assay, resolved via standard 8 to 15% SDS-PAGE, and transferred to PVDF membrane. Blots were probed with the indicated primary and corresponding secondary HRPantibodies, and then exposed to X-ray film following incubation with ECL; or with a digital detection system (Kindle Biosciences) following incubation with digital ECL. Protein levels were quantified using ImageJ vl.54i.

[0146] Translation assays: Analysis of de novo protein synthesis was performed as described previously in the art. (See Ref. No. 9 & 11). In brief, cells were grown for 1 hr in methionine free media, followed by addition of L-azidohomoalanine (AHA, 50 pM final) (Invitrogen C10102) plus vehicle or SVC 112 (1 pM final) for 2 hr. Protein isolation, quantification, florescent AHA labeling, and SDS-PAGE resolution was performed using a Click-iT Tetramethylrhodamine (TAMRA) Protein Analysis Detection Kit (Invitrogen C33370) following manufacturer’s instructions. TAMRA labeled proteins were visualized via UV excitation, total protein via Coomassie staining, with digital image acquisition (ChemiDoc MP, BioRad). Relative de novo protein levels was determined using ImageJ vl.54i. Analysis of in vitro translation was performed as described previously 9. In brief, uncapped IRES driven Luciferase mRNA (Pierce L4561) was translated for 90 min at 37°C in the presence of vehicle, SVC112 or HHT, with rabbit reticulocyte lysate (Pierce L4960) according to manufacturer’s instructions. Luciferase activity was assayed using a Luciferase Assay System kit (Pierce El 500) and a plate reader (Synergy 2, BioTek) according to manufacturer’s instructions. ICso was calculated using non-linear regression in Prism (GraphPad Software).

[0147] Flow cytometry: Apoptotic index assays were performed as described previously (See Ref. No.37-39). In brief, cells were treated with vehicle or SVC 112 for 6 hr, washed in PBS and allowed to recover in drug-free media for 18 and 42 hr, then washed in PBS, resuspended inAnnexin V Binding Buffer, stained with Annexin V-FITC (BD Biosciences 556420) and Propidium iodide (Sigma-Aldrich P5368), and analyzed with a flow cytometer (MACSQuant VYB, Miltenyi Biotec).

[0148] Animal Studies: Cell line-derived xenografts were performed as described previously (See Ref. No. 9 & 40). For the experiment in Fig. 3A, 107 MV-4-11 cells per mouse mixed 1:1 with Matrigel Matrix in 100 pl total volume were inoculated by subcutaneous injection into the right hind flank of BALB / c nude mice (6-8 weeks old females, Peking Vital River Laboratory Animal Co.). For Fig. 3B, 5X106MV-4-11 cells per mouse in 100 pl PBS were inoculated into the tail vein of NOG mice (6-8 weeks old females, Peking Vital River Laboratory Animal Co.) and treatment started 2 weeks after inoculation. For Fig. 3C / D, Fig 4D, and Fig.6, 1X106 AML-EOL-1, MV-4-11 or DLD-1, or 5X105HCT116 cells per mouse mixed 1:1 with Matrigel in 100 pl total volume were inoculated by subcutaneous injection into the right hind flank of nu / nu mice (5-8 weeks old females, Charles River Laboratory). Mice were randomized into treatment groups before the first dose. Average tumor volumes at the start of treatment were 104.3 mm3(MV-4-11, Fig. 3A), 169.8 mm3(MV-4-11, Fig. 6), 140.3 mm3(AML-EOL-1, Fig. 3C), 182.6 mm3 (HCT116, Fig. 3D) and 127.3 mm3(DLD-1, Fig. 4D). For flank implantation, individual tumor volumes were tracked until they exceeded the institutional limit of 2000 mm3, at which point animals were euthanized. For orthotopic implantation, treatment began 2 weeks after implantation, and survival was tracked until animal death or moribundity. QDX5= 5 days on, 2 days off. SVC112 was administered in a previously described nanosuspension formulation (Fig. 3A / B) or in a DMA (N,NDimethylacetamide)-based solution formulation (all other animal studies), which pharmacokinetics studies show is more bio-available and therefore requires less drug in solution to achieve similar exposure as drug in nanosuspension. In alternative embodiments, DMA can be substituted with N-methylpyrrolidone (NMP).

[0149] Animal studies conducted at WuXi AppTec (Fig. 3A / B) were performed in compliance with the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec, and the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), using experimental protocols that conformed to relevant institutional guidelines and regulations. All other animal studies were conducted at the University of Colorado, Boulder, in compliance with the IACUC of the University of Colorado, and in adherence to Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, using experimental protocols that conformed to relevantinstitutional guidelines and regulations. Method of euthanasia was CO2 asphyxiation followed by cervical dislocation.

[0150] Sample size calculation for xenograft experiments: Animal numbers needed were calculated based on the following criteria: 1) the mean tumor volume for controls is estimated to be 1500 cm3when the first animals reach the institutional limit of 2000 cm3, with a Standard Devia2on (SD) of 25% or 375 cm3. 2) to detect a 2-fold decrease in tumor size (effect size of 750 cm3), with 5% type 1 error (p=0.05, 2-tailed t-test) and 80% power, a minimum of 3.9 animals per arm was required. All xenograft experiments meet this requirement except for the pilot feasibility study assessing the DMA-based SVC112 solution formulation.

[0151] Statistical analysis: Data for animal studies are presented as the mean ±1 standard error of the mean (SEM). Probability was calculated in Prism (GraphPad Software) via unpaired t-test from the last day shown on the graphs (tumor volume) or Log-rank test (Kaplan-Meier plots). Probability values shown correspond to * P < 0.05, ** P < 0.01, *** P < 0.001, **** p < 0.0001. For all other studies error bars represent the mean ±1 standard deviation (STD).REFERENCES

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Claims

CLAIMSWhat is claimed is1. A method of treating a cancer in a patient in need thereof, the method comprising administering to the patient SVC112, or pharmaceutically acceptable salt or solvate thereof.

2. A method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising SVC 112, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.

3. The method of claim 1 or 2, wherein the cancer is a solid tumor.

4. The method of any one of the preceding claims, wherein the cancer is selected from multiple myeloma, gastrointestinal cancer, salivary gland cancer, or leukemia.

5. The method of claim 4, wherein the cancer is leukemia.

6. The method of claim 5, wherein the leukemia is chronic lymphocytic leukemia (CLL), hairy cell leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or chronic myelomonocytic leukemia (CMML).

7. The method of claim 6, wherein the leukemia is acute myeloid leukemia (AML).

8. The method of any one of claims 5-7, wherein the cancer is characterized as having an oncogenic TP53, FLT3, MLL fusion, CDKN2A, NRAS, DNMT3A, NPM1 alteration, or any combination thereof.

9. The method of claim 8, wherein the cancer is characterized as having an oncogenic TP53 alteration.

10. The method of claim 8, wherein the cancer is characterized as having an oncogenic FLT3 alteration.

11. The method of claim 8, wherein the cancer is characterized as having an oncogenic MLL fusion alteration.

12. The method of claim 8, wherein the cancer is characterized as having an oncogenic CDKN2A alteration.

13. The method of claim 12, wherein the oncogenic CDKN2A alteration is a CDKN2A P84 mutation, and wherein the CDKN2A P84 mutation comprises a P84L substitution.

14. The method of claim 8, wherein the cancer is characterized as having an oncogenic NRAS alteration.

15. The method of claim 14, wherein the oncogenic NRAS alteration is a NRAS Q61L mutation.

16. The method of claim 8, wherein the cancer is characterized as having an oncogenic DNMT3A alteration.

17. The method of claim 16, wherein the oncogenic DNMT3A alteration is a DNMT3A R882C mutation.

18. The method of claim 8, wherein the cancer is characterized as having an oncogenic NPM1 alteration.

19. The method of claim 18, wherein the oncogenic NPM1 alteration is a NPM1 W288C mutation.

20. The method of claim 4, wherein the cancer is multiple myeloma.

21. The method of claim 20, wherein the multiple myeloma is light chain myeloma, non- secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, IgD myeloma, or IgE myeloma.

22. The method of claim 20 or 21, wherein the cancer is characterized as having an oncogenic NRAS, TP53, PIK3CA, EGFR, KRAS, TRAF3, CDKN2A, FGFR3, SMAD2, BRAF, MSH6 alteration, or any combination thereof.

23. The method of claim 22, wherein the cancer is characterized as having an oncogenic NRAS alteration.

24. The method of claim 23, wherein the oncogenic NRAS alteration is a NRAS G13D mutation, a NRAS Q61H mutation, or any combination thereof.

25. The method of claim 22, wherein the cancer is characterized as having an oncogenic TP53 alteration.

26. The method of claim 25, wherein the oncogenic TP53 alteration is a TP53 A161T mutation, a TP53 R175H mutation, a TP53 S261T mutation, a TP53 E285L mutation, or any combination thereof.

27. The method of claim 22, wherein the cancer is characterized as having an oncogenic PIK3CA alteration.

28. The method of claim 27, wherein the oncogenic PIK3CA alteration is a PIK3CA E545K mutation.

29. The method of claim 22, wherein the cancer is characterized as having an oncogenic EGFR alteration.

30. The method of claim 29, wherein the oncogenic EGFR alteration is an EGFR T751I mutation.

31. The method of claim 22, wherein the cancer is characterized as having an oncogenic KRAS alteration.

32. The method of claim 31, wherein the oncogenic KRAS alteration is a KRAS G12A mutation.

33. The method of claim 22, wherein the cancer is characterized as having an oncogenic TRAF3 alteration.

34. The method of claim 33, wherein the oncogenic TRAF3 alteration is a TRAF3 K191L mutation, a TRAF3 K55OL mutation, or any combination thereof.

35. The method of claim 22, wherein the cancer is characterized as having an oncogenic CDKN2A alteration.

36. The method of claim 35, wherein the oncogenic CDKN2A alteration is a CDKN2A H83Y mutation.

37. The method of claim 22, wherein the cancer is characterized as having an oncogenic FGFR3 alteration.

38. The method of claim 37, wherein the oncogenic FGFR3 alteration is a FGFR3 K650E mutation.

39. The method of claim 22, wherein the cancer is characterized as having an oncogenic SMAD2 alteration.

40. The method of claim 39, wherein the oncogenic SMAD2 alteration is a SMAD2 L87R mutation.

41. The method of claim 22, wherein the cancer is characterized as having an oncogenic BRAF alteration.

42. The method of claim 41, wherein the oncogenic BRAF alteration is a Class I BRAF mutation.

43. The method of claim 41, wherein the oncogenic BRAF alteration is a Class TI BRAF mutation.

44. The method of claim 41, wherein the oncogenic BRAF alteration is a Class III BRAF mutation.

45. The method of claim 41, wherein the oncogenic BRAF alteration is a BRAF K601N mutation.

46. The method of claim 22, wherein the cancer is characterized as having an oncogenic MSH6 alteration.

47. The method of claim 46, wherein the oncogenic MSH6 alteration is a MSH6 G141D mutation.

48. The method of claim 4, wherein the cancer is gastrointestinal cancer.

49. The method of claim 48, wherein the gastrointestinal cancer is colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, or esophageal cancer.

50. The method of claim 49, wherein the gastrointestinal cancer is colon cancer.

51. The method of claim 49, wherein the gastrointestinal cancer is rectal cancer.

52. The method of claim 49, wherein the gastrointestinal cancer is pancreatic cancer.

53. The method of claim 49, wherein the gastrointestinal cancer is liver cancer.

54. The method of claim 49, wherein the gastrointestinal cancer is esophageal cancer.

55. The method of claim 49, wherein the gastrointestinal cancer is colorectal cancer, and wherein the colorectal cancer comprises colorectal adenocarcinoma.

56. The method of claim 55, wherein the cancer is characterized as having an oncogenic APC, ACVR2A, KRAS, TP53, PIK3CA, BRAF, TGFBR2, CDKN2A, BRCA2, CTNNB1, PPM1D, EP300, SMAD4 alteration, or any combination thereof.

57. The method of claim 56, wherein the cancer is characterized as having an oncogenic APC alteration.

58. The method of claim 57, wherein the oncogenic APC alteration is a APC R856C mutation, a APC T1556N mutation, a APC R2714C mutation, or any combination thereof.

59. The method of claim 56, wherein the cancer is characterized as having an oncogenic ACVR2A alteration.

60. The method of claim 59, wherein the oncogenic ACVR2A alteration is a ACVR2A K437R mutation.

61. The method of claim 56, wherein the cancer is characterized as having an oncogenic KRAS alteration.

62. The method of claim 56, wherein the oncogenic KRAS alteration is a KRAS G13D mutation.

63. The method of claim 56, wherein the cancer is characterized as having an oncogenic TP53 alteration.

64. The method of claim 63, wherein the oncogenic TP53 alteration is a TP53 S 127P mutation, a TP53 K382N mutation, or any combination thereof.

65. The method of claim 56, wherein the cancer is characterized as having an oncogenic PIK3CA alteration.

66. The method of claim 65, wherein the oncogenic PIK3CA alteration is a PIK3CA P499T mutation, a PIK3CA H1047R mutation, or any combination thereof.

67. The method of claim 56, wherein the cancer is characterized as having an oncogenic BRAF alteration.

68. The method of claim 67, wherein the oncogenic BRAF alteration is a Class I BRAF mutation.

69. The method of claim 67, wherein the oncogenic BRAF alteration is a Class II BRAF mutation.

70. The method of claim 67, wherein the oncogenic BRAF alteration is a Class III BRAF mutation.

71. The method of claim 67, wherein the oncogenic BRAF alteration is a BRAF V600E mutation.

72. The method of claim 56, wherein the cancer is characterized as having an oncogenic TGFBR2 alteration.

73. The method of claim 72, wherein the oncogenic TGFBR2 alteration is a TGFBR2 K128S mutation, a TGFBR2 L453P mutation, or any combination thereof.

74. The method of claim 56, wherein the cancer is characterized as having an oncogenic CDKN2A alteration.

75. The method of claim 74, wherein the oncogenic CDKN2A alteration is a CDKN2A R24S mutation, a CDKN2A E33R mutation, or any combination thereof.

76. The method of claim 56, wherein the cancer is characterized as having an oncogenic BRCA2 alteration.

77. The method of claim 76, wherein the oncogenic BRCA2 alteration is a BRCA2 I2675N mutation.

78. The method of claim 56, wherein the cancer is characterized as having an oncogenic CTNNB1 alteration.

79. The method of claim 56, wherein the cancer is characterized as having an oncogenic PPM ID alteration.

80. The method of claim 56, wherein the cancer is characterized as having an oncogenic EP300 alteration.

81. The method of claim 80, wherein the oncogenic EP300 alteration is a EP300 M147S mutation, a EP300 N1700T mutation, or any combination thereof.

82. The method of claim 56, wherein the cancer is characterized as having an oncogenic SMAD4 alteration.

83. The method of any one of the preceding claims, wherein the cancer is metastatic.

84. The method of any one of the preceding claims, wherein the method is adjuvant therapy following surgical resection.

85. The method of any one of the preceding claims, wherein the method is adjuvant therapy to radiotherapy.

86. The method of any one of the preceding claims, wherein the patient has relapsed after prior therapy.

87. The method of any one of the preceding claims, wherein the patient has acquired resistance to prior therapy.

88. The method of any one of the preceding claims, wherein the patient is refractory to prior therapy.

89. A method of treating a cancer in a patient in need thereof, the method comprising administering to the patient:(a) a composition comprising SVC112, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one oncology therapeutic selected from a BCL-2 inhibitor, a BCL-XL inhibitor, and an ERK inhibitor.

90. The method of claim 89, wherein the at least one oncology therapeutic is a BCL-2 inhibitor.

91. The method of claim 90, wherein the BCL-2 inhibitor is venetoclax.

92. The method of claim 89, wherein the least one oncology therapeutic is a BCL-XL inhibitor.

93. The method of claim 89, wherein the at least one oncology therapeutic is an ERK inhibitor.

94. The method of claim 93, wherein the ERK inhibitor is ulixertinib.

95. The method of any one of claims 89-95, wherein the cancer is a solid tumor.

96. The method of any one of claims 89-95, wherein the cancer is selected from multiple myeloma, gastrointestinal cancer, or leukemia.

97. The method of claim 96, wherein the cancer is leukemia.

98. The method of claim 97, wherein the leukemia is chronic lymphocytic leukemia (CLL), hairy cell leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or chronic myelomonocytic leukemia (CMML).

99. The method of claim 98, wherein the leukemia is acute myeloid leukemia (AML).

100. The method of claim 98 or 99, wherein the cancer is characterized as having an oncogenic TP53, FLT3, MLL fusion, CDKN2A, NRAS, DNMT3A, NPM1 alteration, or any combination thereof.

101. The method of claim 100, wherein the cancer is characterized as having an oncogenic TP53 alteration.

102. The method of claim 100, wherein the cancer is characterized as having an oncogenic FLT3 alteration.

103. The method of claim 100, wherein the cancer is characterized as having an oncogenic MLL fusion alteration.

104. The method of claim 100, wherein the cancer is characterized as having an oncogenic CDKN2A alteration.

105. The method of claim 104, wherein the oncogenic CDKN2A alteration is a CDKN2A P84L mutation.

106. The method of claim 100, wherein the cancer is characterized as having an oncogenic NRAS alteration.

107. The method of claim 106, wherein the oncogenic NRAS alteration is a NRAS Q61L mutation.

108. The method of claim 100, wherein the cancer is characterized as having an oncogenic DNMT3A alteration.

109. The method of claim 108, wherein the oncogenic DNMT3A alteration is a DNMT3A R882C mutation.

110. The method of claim 100, wherein the cancer is characterized as having an oncogenic NPM1 alteration.

111. The method of claim 110, wherein the oncogenic NPM1 alteration is a NPM1 W288C mutation.

112. The method of claim 96, wherein the cancer is multiple myeloma.

113. The method of claim 112, wherein the multiple myeloma is light chain myeloma, non- secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, IgD myeloma, or IgE myeloma.

114. The method of claim 112 or 113, wherein the cancer is characterized as having an oncogenic NRAS, TP53, PIK3CA, EGFR, KRAS, TRAF3, CDKN2A, FGFR3, SMAD2, BRAF, MSH6 alteration, or any combination thereof.

115. The method of claim 114, wherein the cancer is characterized as having an oncogenic NRAS alteration.

116. The method of claim 115, wherein the oncogenic NRAS alteration is a NRAS G13D mutation, a NRAS Q61H mutation, or any combination thereof.

117. The method of claim 104, wherein the cancer is characterized as having an oncogenic TP53 alteration.

118. The method of claim 117, wherein the oncogenic TP53 alteration is a TP53 A161T mutation, a TP53 R175H mutation, a TP53 S261T mutation, a TP53 E285L mutation, or any combination thereof.

119. The method of claim 114, wherein the cancer is characterized as having an oncogenic PIK3CA alteration.

120. The method of claim 119, wherein the oncogenic PIK3CA alteration is a PIK3CA E545K mutation.

121. The method of claim 114, wherein the cancer is characterized as having an oncogenic EGFR alteration.

122. The method of claim 121, wherein the oncogenic EGFR alteration is a EGFR T751I mutation.

123. The method of claim 114, wherein the cancer is characterized as having an oncogenic KRAS alteration.

124. The method of claim 123, wherein the oncogenic KRAS alteration is a KRAS G12A mutation.

125. The method of claim 114, wherein the cancer is characterized as having an oncogenic TRAF3 alteration.

126. The method of claim 125, wherein the oncogenic TRAF3 alteration is a TRAF3 K191L mutation, a TRAF3 K55OL mutation, or any combination thereof.

127. The method of claim 114, wherein the cancer is characterized as having an oncogenic CDKN2A alteration.

128. The method of claim 127, wherein the oncogenic CDKN2A alteration is a CDKN2A H83 Y mutation.

129. The method of claim 114, wherein the cancer is characterized as having an oncogenic FGFR3 alteration.

130. The method of claim 129, wherein the oncogenic FGFR3 alteration is a FGFR3 K650E mutation.

131. The method of claim 114, wherein the cancer is characterized as having an oncogenic SMAD2 alteration.

132. The method of claim 131, wherein the oncogenic SMAD2 alteration is a SMAD2 L87R mutation.

133. The method of claim 114, wherein the cancer is characterized as having an oncogenic BRAF alteration.

134. The method of claim 133, wherein the oncogenic BRAF alteration is a Class I BRAF mutation.

135. The method of claim 133, wherein the oncogenic BRAF alteration is a Class II BRAF mutation.

136. The method of claim 133, wherein the oncogenic BRAF alteration is a Class III BRAF mutation.

137. The method of claim 133, wherein the oncogenic BRAF alteration is a BRAF K601N mutation.

138. The method of claim 114, wherein the cancer is characterized as having an oncogenic MSH6 alteration.

139. The method of claim 138, wherein the oncogenic MSH6 alteration is a MSH6 G141D mutation.

140. The method of claim 96, wherein the cancer is gastrointestinal cancer.

141. The method of claim 140, wherein the gastrointestinal cancer is colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, or esophageal cancer.

142. The method of claim 141, wherein the gastrointestinal cancer is colon cancer.

143. The method of claim 141, wherein the gastrointestinal cancer is rectal cancer.

144. The method of claim 141, wherein the gastrointestinal cancer is pancreatic cancer.

145. The method of claim 141, wherein the gastrointestinal cancer is liver cancer.

146. The method of claim 141, wherein the gastrointestinal cancer is esophageal cancer.

147. The method of claim 141, wherein the gastrointestinal cancer is colorectal cancer, and wherein the colorectal cancer comprises colorectal adenocarcinoma.

148. The method of claim 147, wherein the cancer is characterized as having an oncogenic APC, ACVR2A, KRAS, TP53, PIK3CA, BRAF, TGFBR2, CDKN2A, BRCA2, CTNNB1, PPM1D, EP300, SMAD4 alteration, or any combination thereof.

149. The method of claim 148, wherein the cancer is characterized as having an oncogenic APC alteration.

150. The method of claim 149, wherein the oncogenic APC alteration is a APC R856C mutation, a APC T1556N mutation, a APC R2714C mutation, or any combination thereof.

151. The method of claim 148, wherein the cancer is characterized as having an oncogenic ACVR2A alteration.

152. The method of claim 151, wherein the oncogenic ACVR2A alteration is a ACVR2A K437R mutation.

153. The method of claim 148, wherein the cancer is characterized as having an oncogenic KRAS alteration.

154. The method of claim 153, wherein the oncogenic KRAS alteration is a KRAS G13D mutation.

155. The method of claim 148, wherein the cancer is characterized as having an oncogenic TP53 alteration.

156. The method of claim 155, wherein the oncogenic TP53 alteration is a TP53 S127P mutation, a TP53 K382N mutation, or any combination thereof.

157. The method of claim 148, wherein the cancer is characterized as having an oncogenic PIK3CA alteration.

158. The method of claim 157, wherein the oncogenic PIK3CA alteration is a PIK3CA P499T mutation, a PIK3CA H1047R mutation, or any combination thereof.

159. The method of claim 148, wherein the cancer is characterized as having an oncogenic BRAF alteration.

160. The method of claim 159, wherein the oncogenic BRAF alteration is a Class I BRAF mutation.

161. The method of claim 159, wherein the oncogenic BRAF alteration is a Class II BRAF mutation.

162. The method of claim 159, wherein the oncogenic BRAF alteration is a Class III BRAF mutation.

163. The method of claim 159, wherein the oncogenic BRAF alteration is a BRAF V600E mutation.

164. The method of claim 148, wherein the cancer is characterized as having an oncogenic TGFBR2 alteration.

165. The method of claim 164, wherein the oncogenic TGFBR2 alteration is a TGFBR2 K128S mutation, a TGFBR2 L453P mutation, or any combination thereof.

166. The method of claim 148, wherein the cancer is characterized as having an oncogenic CDKN2A alteration.

167. The method of claim 166, wherein the oncogenic CDKN2A alteration is a CDKN2A R24S mutation, a CDKN2A E33R mutation, or any combination thereof.

168. The method of claim 148, wherein the cancer is characterized as having an oncogenic BRCA2 alteration.

169. The method of claim 168, wherein the oncogenic BRCA2 alteration is a BRCA2 I2675N mutation.

170. The method of claim 148, wherein the cancer is characterized as having an oncogenic CTNNB1 alteration.

171. The method of claim 148, wherein the cancer is characterized as having an oncogenic PPM ID alteration.

172. The method of claim 148, wherein the cancer is characterized as having an oncogenic EP300 alteration.

173. The method of claim 172, wherein the oncogenic EP300 alteration is a EP300 M147S mutation, a EP300 N1700T mutation, or any combination thereof.

174. The method of claim 143, wherein the cancer is characterized as having an oncogenic SMAD4 alteration.

175. The method of any one of claims 89-174, wherein the cancer is metastatic.

176. The method of any one of claims 89-175, wherein the method is adjuvant therapy following surgical resection.

177. The method of any one of claims 89-176, wherein the method is adjuvant therapy to radiotherapy.

178. The method of any one of claims 89-177, wherein the patient has relapsed after prior therapy.

179. The method of any one of claims 89-178, wherein the patient has acquired resistance to prior therapy.

180. The method of any one of claims 89-179 wherein the patient is refractory to prior therapy.

181. The method of any one of the preceding claims, wherein the SVC 112, or pharmaceutically acceptable salt or solvate thereof, is administered intravenously.

182. The method of any one of claims 1-181, wherein the SVC112, or pharmaceutically acceptable salt or solvate thereof, is administered as a pharmaceutical composition suitable for intravenous administration comprising SVC112, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier.

183. The method of claim 182, wherein the pharmaceutically acceptable carrier is selected from dimethyacetamide (DMA), Cremaphor EL (CrEL), N-methylpyrrolidone (NMP), a cyclodextrin, or a combination thereof.

184. The method of claim 183, wherein the pharmaceutical composition comprises DMA and CrEL in a saline solution of a concentration of about 0.45% to about 1.35% DMA.

185. The method of claim 183, wherein the pharmaceutical composition comprises DMA and CrEL in about a 2:1 ratio in a saline solution of a concentration of about 0.9% NaCl.

186. The method of any of the preceding claims where the patient is sensitive to treatment with SVC112 based on a measurement of a biological sample from the patient indicating they have a level of MCL-1 that is above a predetermined threshold.

187. The method of any of the preceding claims where the patient is sensitive to treatment with SVC112 based on a measurement of a biological sample from the patient indicating they have a level of BCL-XL that is below a predetermined threshold.

188. The method of any of the preceding claims where the patient is sensitive to treatment with SVC112 based on a measurement of a biological sample from the patient indicating they have a level of phosphorylation of c-Myc at position Ser62 that is below a predetermined threshold.

189. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a translation elongation inhibitor based on the level of at least one biomarker in a biological sample from the subject, wherein the biomarkers are selected from MCL-1, BCL-XL and c-Myc.

190. The method of claim 189, wherein the level of the biomarker is the protein expression level of MCL-1, or BCL-XL.

191. The method of claim 189, wherein the level of the biomarker is the activity level of MCL- 1, BCL-XL, or c-Myc.

192. The method of claim 189, wherein the level of the biomarker is the transcription level of MCL-1, or BCL-XL.

193. The method of claim 189, wherein the level of the biomarker is the phosphorylation level of c-Myc at position Ser62.

194. The method of claim 1189, wherein the biological sample is from a subject having a cancer selected from: leukemia, or colorectal cancer (CRC).

195. The method of claim 194, the leukemia is selected from acute myeloid leukemia (AML).

196. The method of claim 189, wherein the subject is a human patient.

197. The method of claim 189, wherein the biomarker level is determined based on a control population of cancer patients who have responded to translation elongation inhibitor treatment.

198. The method of claim 189, wherein the biomarker level is determined based on a control population of cancer patients who have not responded to translation elongation inhibitor treatment.

199. The method of any of claims 196-198, wherein the human patient is sensitive to with the translation elongation inhibitor treatment:- if the level of MCL-1 is above a predetermined threshold- if the level of BCL-XL is below a predetermined threshold; or- if the level of phosphorylation of c-Myc at position Ser62 is below a predetermined threshold.

200. The method of any of claims 189-199, wherein the translation elongation inhibitor is SVC112, or pharmaceutically acceptable salt or solvate thereof.

201. The method of any of claims 189-200, further comprising administering a therapeutically effective amount of at least one oncology therapeutic selected from a BCL-2 inhibitor, a BCL-XL inhibitor, and an ERK inhibitor.

202. The method of claim 201, wherein the BCL-2 inhibitor is venetoclax.

203. The method of claim 201, wherein the ERK inhibitor is ulixertinib.

204. A method for determining the sensitivity or resistance of a cancer subject to treatment with an translation elongation inhibitor, the method comprising:- obtaining a biological sample from the subject;- measuring the level of one or more biomarkers in a biological sample obtained from a subject, wherein the one or more biomarkers is selected from: MCL-1, BCL-XL, and c-Myc;- determining that the patient is:- sensitive to the treatment if the level of MCL-1 is above a predetermined threshold, or is resistant to the treatment if the level of MCL-1 is below the predetermined threshold;- sensitive the treatment if the level of BCL-XL is below a predetermined threshold, or is resistant to the treatment if the level of BCL-XL is above the predetermined threshold; or- sensitive to the treatment if the level of phosphorylation of c-Myc at position Ser62 is below a predetermined threshold, or is resistant the treatment if the level of phosphorylation of c-Myc at position Ser62 is above the predetermined threshold; and- administering a therapeutically effective amount of a translation elongation inhibitor to the subject determined to be sensitive based on the level of the at least one of the biomarkers.

205. The method of claim 204, wherein the biological sample is from a subject having a cancer selected from: leukemia, or colorectal cancer (CRC).

206. The method of claim 204, the leukemia is selected from acute myeloid leukemia (AML).

207. The method of any of claims 204-206, wherein the biological sample is selected from:blood, plasma, serum, tumor tissue, or a biopsy sample.

208. The method of claim 204, wherein the subject is a human patient.

209. The method of claim 204, wherein the level of biomarker is measured using an assay selected from the group consisting of enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR), western blot, or RNA sequencing.

210. The method of claim 204, wherein the predetermined threshold is determined based on a control population of cancer patients who have responded to translation elongation inhibitor treatment.

211. The method of claim 204, wherein the predetermined threshold is determined based on a control population of cancer patients who have not responded to translation elongation inhibitor treatment.

212. The method of any of claims 204-211, wherein the translation elongation inhibitor is SVC 112, or pharmaceutically acceptable salt or solvate thereof.

213. The method of any of claims 204-212, further comprising administering a therapeutically effective amount of at least one oncology therapeutic selected from a BCL-2 inhibitor, a BCL-XL inhibitor, and an ERK inhibitor.

214. The method of claim 213, wherein the BCL-2 inhibitor is venetoclax.

215. The method of claim 213, wherein the ERK inhibitor is ulixertinib.

216. A method for optimizing cancer treatment in a subject in need thereof, comprising:- measuring the level of one or more biomarkers in a biological sample obtained from the subject, wherein the one or more biomarkers are selected from: MCL-1, BCL-XL, and c- Myc;- classifying the subject as a responder or non-responder to treatment with a translation elongation inhibitor based on the measured level of the at least one or more biomarkers, wherein the subject is:- sensitive to the treatment if the level of MCL-1 is above a predetermined threshold, or is resistant to the treatment if the level of MCL-1 is below the predetermined threshold;- sensitive the treatment if the level of BCL-XL is below a predetermined threshold, or is resistant to the treatment if the level of BCL-XL is above the predetermined threshold; or- sensitive to the treatment if the level of phosphorylation of c-Myc at position Ser62is below a predetermined threshold, or is resistant the treatment if the level of phosphorylation of c-Myc at position Ser62 is above the predetermined threshold; and- selecting a treatment regimen comprising administering the translation elongation inhibitor if the patient is classified as sensitive, or selecting an alternative treatment if the patient is classified as resistant.

217. The method of claim 216, wherein the alternative treatment is selected from chemotherapy, targeted therapy, immunotherapy, or radiation therapy.

218. The method of claim 216, wherein the predetermined threshold of MCL-1 is compared to a reference standard obtained from a population of known translation elongation inhibitor responders and non-responders.

219. The method of claim 216, wherein the predetermined threshold of BCL-XL is compared to a reference standard obtained from a population of known translation elongation inhibitor responders and non-responders.

220. The method of claim 216, wherein the predetermined threshold of phosphorylation of c- Myc at position Ser62 is compared to a reference standard obtained from a population of known translation elongation inhibitor responders and non-responders.

221. The method of claim 216, wherein the biological sample is from a subject having a cancer selected from: leukemia, or colorectal cancer (CRC).

222. The method of claim 221, the leukemia is selected from acute myeloid leukemia (AML).

223. The method of any of claims 216-222, wherein the biological sample is selected from:blood, plasma, serum, tumor tissue, or a biopsy sample.

224. The method of claim 216, wherein the subject is a human patient.

225. The method of claim 216, wherein the level of biomarker is measured using an assay selected from the group consisting of enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR), western blot, or RNA sequencing.

225. The method of any of claims 216-225, wherein the translation elongation inhibitor is SVC112, or pharmaceutically acceptable salt or solvate thereof.

226. The method of any of claims 216-225, further comprising administering a therapeutically effective amount of at least one oncology therapeutic selected from a BCL-2 inhibitor, a BCL-XL inhibitor, and an ERK inhibitor.

227. The method of claim 226, wherein the BCL-2 inhibitor is venetoclax.

228. The method of claim 226, wherein the ERK inhibitor is ulixertinib.

222. A diagnostic kit for determining the sensitivity or resistance of a cancer patient to treatment with a translation elongation inhibitor, comprising:- reagents for detecting and quantifying one or more biomarkers selected from MCL- 1 , BCL- XL, and c-Myc levels in a biological sample; and- instructions for interpreting the results to determine whether the patient is sensitive or resistant to translation elongation inhibitor based on the biomarker level.

223. The kit of claim 222, wherein the level of the biomarker is the activity level of MCL- 1, or BCL-XL.

224. The kit of claim 222, wherein the level of the biomarker is the transcription level of MCL- 1, or BCL-XL.

225. The kit of claim 222, wherein the level of the biomarker is the phosphorylation level of c- Myc at position Ser62.

226. The kit of claim 222, wherein the biological sample is from a subject having a cancer selected from: leukemia, or colorectal cancer (CRC).

227. The kit of claim 226, the leukemia is selected from acute myeloid leukemia (AML), multiple myeloma (MM).

228. The kit of claim 222, wherein the subject is a human patient.

229. The kit of claim 222, wherein the biomarker level is determined based on a control population of cancer patients who have responded to translation elongation inhibitor treatment.

230. The kit of claim 222, wherein the biomarker level is determined based on a control population of cancer patients who have not responded to translation elongation inhibitor treatment.

231. The kit of claim 222, wherein the reagents for detecting and quantifying one or more biomarkers comprise reagents for detecting and quantifying one or more biomarkers using an assay selected from the group consisting of enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR), western blot, or RNA sequencing.

234. The kit of any of claims 222-231, wherein the translation elongation inhibitor is SVC112.

235. The method of any of claims 1-228, further comprising administering a therapeutically effective amount of radiation therapy to the subject in need thereof.

236. The method of claim 235, wherein the therapeutically effective amount of radiation therapy is administered to the subject prior to, concurrent with, or after administration of the SVC 112.

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