Use of RXR agonists in the treatment of HER2+ cancers

Abstract

This disclosure relates to Her2 + Provided is a combination of active agents and related therapies for the improved treatment of cancer, comprising an RXR agonist and a Her2 targeted therapeutic, and optionally further comprising thyroid hormone.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 286,981, filed December 7, 2021, the entire contents of which are incorporated herein by reference.

[0002] (STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH) This invention was made with United States government support under Grant No. HHSN261201500018I from the National Institutes of Health. The United States government has certain rights in the invention. [Background technology]

[0003] Compounds having retinoid-like biological activity are well known in the art and are described in numerous United States patents, including, but not limited to, U.S. Patent Nos. 5,466,861, 5,675,033, and 5,917,082, all of which are incorporated herein by reference. Preclinical studies suggest that selective activation of the retinoid X receptor (RXR), which regulates functions related to differentiation, inhibition of cell proliferation, apoptosis, and metastasis, by RXR agonists (rexinoids) is useful in the treatment of a variety of diseases associated with biochemical functions regulated by RXR.

[0004] For example, TARGRETIN® (bexarotene), a retinoid X receptor (RXR) agonist that also has retinoic acid receptor (RAR) agonist activity, has been approved by the U.S. Food and Drug Administration for oral and topical treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients refractory to at least one prior systemic therapy. TARGRETIN® has shown promising results in multiple Phase II trials in non-small cell lung cancer (NSCLC). However, a pivotal Phase III clinical trial failed to demonstrate improved survival. One reason for the limited success of bexarotene may be that activation of RAR reduces its efficacy as an anticancer drug. Thus, more selective RXR agonists may hold more promise.

[0005] Drugs targeting human epidermal growth factor receptor 2 (Her2), both anti-Her2 antibodies and inhibitors of Her2 tyrosine kinase activity, have been shown to inhibit Her2 + Cancer, especially Her2 + It has provided significant, but not unbiased, success in the treatment of breast cancer.

[0006] Cancer treatments are constantly evolving, becoming more specialized and sophisticated. Early non-surgical cancer treatments generally targeted rapidly dividing cells, which are more sensitive to radiation and chemical aggressions. Gradually, more specific and generally less toxic treatments have been developed. Some treatments have broad applicability, such as immune checkpoint inhibitors or rexinoids. Others target cancers expressing specific antigens or other biomarkers involved in the control of proliferation or differentiation, including many monoclonal antibodies and kinase inhibitors. However, as the number of cancer treatments increases, it becomes more difficult to determine which treatments to apply to which indications and effective combinations of treatments. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Pat. No. 5,466,861 [Patent Document 2] U.S. Pat. No. 5,675,033 [Patent Document 3] U.S. Pat. No. 5,917,082 Summary of the Invention [Means for solving the problem]

[0008] In this disclosure, Her2 + Cancer, especially Her2 resistant to Her2-targeted drugs + Improved methods of treating cancer are disclosed. These methods include + The present invention includes treating a patient with tumor with a combination of Her2 targeting therapeutic agent and RXR agonist that can inhibit the growth of cancer.In some embodiments, the cancer is also resistant to RXR agonist.In some embodiments, the combination of treatment methods further includes thyroid hormone.

[0009] In some embodiments, the RXR agonist can activate RXR / Nurr1 heterodimer receptor. In some embodiments, the RXR agonist is a compound of formula I disclosed below, or a pharmaceutically acceptable salt thereof. In some embodiments, the RXR agonist is a compound of formula II disclosed below, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of formula I and formula II and their pharmaceutically acceptable salts are referred to as the method of activating RXR / Nurr1 heterodimer receptor or the rexinoid method of inhibiting tumor growth.

[0010] In some embodiments, the Her2 targeted therapeutic is an inhibitor of Her2 kinase activity or Her2-mediated signaling. In some embodiments, the Her2 targeted therapeutic is a therapeutic anti-Her2 antibody. The therapeutic antibody may mediate antibody-dependent cellular cytotoxicity (ADCC) instead of or in addition to inhibiting signaling (kinase activity). As disclosed below, trastuzumab and pertuzumab are examples of therapeutic anti-Her2 antibodies. In some embodiments, such antibodies inhibit Her2 + Immunoglobulin method to inhibit tumor cell proliferation, Her2 + This is referred to as ADCC-mediated therapy of tumor cells or immunoglobulin therapy that inhibits Her2 signaling.

[0011] In some embodiments, the Her2 targeted therapeutic is an antibody drug conjugate that includes an anti-Her2 antibody. In some embodiments, the anti-Her2 antibody alone has therapeutic activity, while in other embodiments, the anti-Her2 antibody alone does not have therapeutic activity and merely targets Her2. + It only serves to deliver cytotoxic agents to cells. As disclosed below, ado-trastuzumab emtansine is an example of a Her2-targeted antibody-drug conjugate. In some embodiments, such an antibody-drug conjugate targets Her2. + It is referred to as a method of delivering cytotoxic drugs to cells.

[0012] In some embodiments, the inhibitor of Her2 kinase activity or Her2-mediated signal transduction is a small organic molecule (small molecule drug) inhibitor of Her2 kinase activity.As disclosed below, lapatinib, neratinib and tucatinib are examples of Her2 kinase inhibitors.In some embodiments, such small molecule drug inhibitor of Her2 kinase activity is referred to as small molecule therapy that inhibits Her2 kinase activity.

[0013] In some embodiments, Her2 + Cancer is Her2 + In some embodiments, the cancer is breast cancer. +Cancer is Her2 + Having ovarian cancer, gastric cancer, lung adenocarcinoma, uterine cancer (such as serous endometrial cancer), stomach cancer or salivary duct cancer.

[0014] In some embodiments, tumor cell proliferation is inhibited by a combination of a Her2 targeted therapeutic and an RXR agonist, and the inhibition of tumor cell proliferation by the combination is greater than the additive inhibitory effect of each of the Her2 targeted therapeutic and the RXR agonist alone.

[0015] In some embodiments, the treatments of the present disclosure are administered in parallel with other medical or radiotherapy. In other embodiments, the treatments of the present disclosure are the exclusive treatments during their administration. In some embodiments, the treatments of the present disclosure serve as debulking therapy in preparation for subsequent surgical removal of the tumor. In some embodiments, the treatments of the present disclosure are applied as adjuvant therapy following surgical removal of the tumor to address any residual or potential recurrent disease.

[0016] Other embodiments include combination drug compositions or formulations that include at least one Her2 targeted therapeutic and at least one RXR agonist that can inhibit cancer growth. In other embodiments, the combination (used in treatment) may include two or more agents of one or the other class (Her2 targeted drug and / or RXR agonist). In still other embodiments, the combination may further include a thyroid hormone. In some embodiments, the thyroid hormone is thyroxine. [Brief description of the drawings]

[0017] [Figure 1A] FIG. 1A is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and trastuzumab, alone and in combination, on a breast cancer cell line, MCF7 cells (FIG. 1A). [Figure 1B]FIG. 1B is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and trastuzumab, alone and in combination, on a breast cancer cell line (SkBr3 cells (FIG. 1B)). [Figure 2A] FIG. 2A is a three-dimensional plot showing the growth inhibitory effect of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line, MCF7 cells (FIG. 2A). [Figure 2B] FIG. 2B is a three-dimensional plot showing the growth inhibitory effect of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line, SkBr3 cells (FIG. 2B). [Figure 2C] FIG. 2C is a three-dimensional plot showing the growth inhibitory effect of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line, BT474 cells (FIG. 2C). [Figure 2D] FIG. 2D is a three-dimensional plot showing the growth inhibitory effect of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line, MDA-MB-361 cells (FIG. 2D). [Figure 3A] FIG. 3A is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line, MCF7 cells (FIG. 3A). [Figure 3B] FIG. 3B is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line, SkBr3 cells (FIG. 3B). [Figure 3C] FIG. 3C is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line, BT474 cells (FIG. 3C). [Figure 3D] FIG. 3D is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line, MDA-MB-361 cells (FIG. 3D). [Figure 4A]Figures 4A and B are three-dimensional plots depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on the Her2+ breast cancer cell line HCC1954, which is resistant to each agent. Figure 4A shows a three-dimensional plot showing the growth inhibitory effects for a matrix of the two agents at various concentrations. [Figure 4B] FIG. 4B shows a linear plot of the same data for various concentrations of neratinib and zero and 1000 nM IRX4204. [Figure 5A] FIG. 5A is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and tucatinib (FIG. 5A), alone and in combination, on the Her2+ breast cancer cell line HCC1954, which is resistant to each agent, respectively. [Figure 5B] FIG. 5B is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and lapatinib (FIG. 5B), alone and in combination, on the Her2+ breast cancer cell line HCC1954, which is resistant to each agent, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Embodiments of the present disclosure provide a combination of retinoid X receptor (RXR) agonists (rexinoids) and Her2-targeted anti-cancer drugs to treat resistant Her2 + Her2 that is resistant to Her2-targeted drugs, such as breast cancer + Methods for treating cancer include: Her2 targeted therapy resistant Her2 + The cancer may be resistant to an RXR agonist. Some embodiments further comprise administering a thyroid hormone in combination with the RXR agonist. Embodiments include administering a Her2 targeted therapy resistant Her2 + In some embodiments, the use of RXR agonists in combination with Her2 targeted anti-cancer drugs or thyroid hormone and Her2 targeted anti-cancer drugs in the treatment of cancer includes Her2 + Cancer is Her2 + It's breast cancer.

[0019] Her2 is sensitive to Her2-targeted drugs + In view of the effectiveness of the combination of a Her2 targeted therapeutic agent and an RXR agonist of the present disclosure in the treatment of cancer, the combination of a Her2 targeted therapeutic agent and an RXR agonist of the present disclosure is effective in treating Her2 that is resistant to the Her2 targeted therapeutic agent. + It is worth noting that these combinations can also be effective against cancers. Moreover, at the appropriate concentrations of the therapeutic agents, the effect of these combinations is greater than additive (i.e., synergistic). It is even more noteworthy that this is true even when the cancer is resistant to RXR agonists.

[0020] Three small molecule drugs that inhibit Her2 kinase activity but are not structurally related analogs, neratinib, lapatinib, and tucatinib, in combination with the RXR agonist IRX4204, inhibited Her2 kinase activity. + The growth inhibitory effect on breast cancer cell lines was tested. Synergistic growth inhibition was observed for all three kinase inhibitors used with IRX4204. Thus, there is a clear class effect for the inhibitor of Her2 kinase activity. In some embodiments, the inhibitor of Her2 kinase activity is a small organic molecule. In some embodiments, the inhibitor of Her2 kinase activity is an antibody, such as trastuzumab (HERCEPTIN®), margetuximab (MARGENZA®), or pertuzumab (PERJETA®).

[0021] The therapeutic methods of the present disclosure include the combined administration of two, three or more therapeutic agents. Furthermore, the administration of one of these agents may be described as being coordinated or concomitant with the other of these agents. Such combination or coordinated or concomitant administration means that the administration method of each of these agents is such that the physiological effects of the agents overlap in time. This does not require that the agents be included in the same composition or formulation, or be administered simultaneously as separate compositions, by the same route of administration, or on the same schedule, although in some embodiments, they may be any of the above. For example, RXR agonists, thyroid hormones, and Her2 kinase inhibitors can be administered on a daily basis, while antibodies are more typically administered at intervals of several weeks.

[0022] Some of the earlier successful targeted cancer therapies target human epidermal growth factor receptor 2 (Her2). Her2 targeted therapies include monoclonal antibodies (mAbs) such as trastuzumab, margetuximab and pertuzumab, and inhibitors of Her2 kinase activity such as lapatinib, neratinib and afatinib, all of which also inhibit epidermal growth factor receptor (EGFR). The rexinoid IRX4204 has shown activity against various cancers in model systems (e.g., US Patent Publication No. 2008-0300312, which is incorporated herein by reference for all that teaches the use of RXR agonists for the treatment of cancer), especially when used in combination with thyroid hormone (e.g., US Patent Publication No. 2008-0300312, which is incorporated herein by reference for all that teaches the use of RXR agonists for the treatment of cancer). In the present disclosure, the combination of IRX4204 and a Her2 targeted therapeutic agent is + Her2 in breast cancer etc. +It has been shown to be particularly effective against cancer.Accordingly, various embodiments include a combination of IRX4204 and Her2 targeting therapeutic agent, and a treatment method that includes administration of both IRX4204 and Her2 targeting therapeutic agent.Some embodiments further include administration of thyroid hormone or thyroid hormone.Other embodiments do not include administration of thyroid hormone or thyroid hormone.

[0023] The Her2 targeted therapeutic agent used in this disclosure is a therapeutic agent that inhibits the proliferation of cancer cells by inhibiting Her2 function. Such agents include mAbs that bind to Her2, antibody drug conjugates that include such mAbs, and Her2 tyrosine kinase activity inhibitors. Collectively, such agents may be referred to as Her2 targeted therapeutic agents. Some embodiments specifically include or are limited to one or more of these classes of drugs, or one or more species within one or more of these classes of drugs. Some embodiments specifically do not include one or more of these classes of drugs, or one or more species within one or more of these classes of drugs. Thus, Her2 targeted therapeutic agents are mAbs that bind to Her2, antibody drug conjugates that include mAbs that bind to Her2, and Her2 tyrosine kinase activity inhibitors. In some embodiments, the mAb in the antibody drug conjugate has therapeutic activity by itself, and in other embodiments, does not have therapeutic activity.

[0024] Many embodiments include administration of a single anti-Her2 mAb, but some embodiments include administration of multiple anti-Her2 mAbs, such as trastuzumab and pertuzumab. Most disclosed embodiments are described as using anti-Her2 mAbs, but in further embodiments, anti-Her2 polyclonal antisera can be used instead of anti-Her2 mAbs. Some embodiments can include administration of additional mAbs targeting other antigens, and some embodiments do not explicitly include administration of other antibodies.

[0025] (Anti-Her2 antibody) Her2 is a growth factor receptor found and associated with various cancers, especially breast cancer, but also gastroesophageal cancer, ovarian cancer, gastric cancer, lung adenocarcinoma, uterine cancer (such as serous endometrial cancer) or salivary duct cancer. Anti-Her2 antibodies are believed to act as anti-cancer agents through a combination of mechanisms of action, including but not limited to, inhibition of Her2-mediated signaling, antibody-dependent cellular cytotoxicity (ADCC) and mediating presentation of tumor antigens by antigen-presenting cells (APCs) such as macrophages, although additional mechanisms of action may exist. The best understood and most clinically advanced anti-Her2 antibodies are trastuzumab, pertuzumab and margetuximab, although the methods of the present disclosure are not limited to these anti-Her2 mAbs.

[0026] In some embodiments, the antibodies are administered by intravenous infusion. In a typical embodiment, the infusion takes place over 30-90 minutes and may be administered at intervals of 1-3 weeks for a period of one year. In some such embodiments, the antibodies are administered at an initial high dose and then at lower doses. In some such embodiments, the initial high dose is twice the amount of the subsequent lower dose. In some such embodiments, the initial dose is a single dose. In other such embodiments, the initial dose is administered multiple times before switching to a subsequent lower dose. Specific examples of dosages and dosing regimens can be found in the prescribing information for HERCEPTIN® and PERJETA®, which are incorporated by reference in their entirety into this disclosure.

[0027] Trastuzumab binds to domain IV of the extracellular segment of Her2. Trastuzumab inhibits the proliferation of cells overexpressing Her2 and mediates ADCC. Biosimilar antibodies of trastuzumab have been developed and are available in some countries and regions.

[0028] Pertuzumab recognizes the extracellular dimerization domain (domain II) of Her2, a distinct epitope from trastuzumab. By preventing ligand-dependent dimerization, it inhibits Her2-mediated signaling, leading to cell growth arrest and apoptosis. Pertuzumab also mediates ADCC. Pertuzumab enhances trastuzumab activity in tumor xenograft models overexpressing Her2.

[0029] Margetuximab recognizes the same epitope as trastuzumab, but has an engineered Fc region that enhances Fc-dependent immune attack mechanisms such as ADCC by increasing binding to activating Fc-gamma receptors (CD16A) and decreasing binding to inhibitory Fc-gamma receptors (CD16B) on immune effector cells, including monocytes, macrophages, dendritic cells, and natural killer (NK) cells.

[0030] Further anti-Her2 mAbs include TrasGEX®, HM2, Hertuzumab and HT-19. TrasGEX® and HM2 were developed as "biobetters" of trastuzumab, while the other two are independent derivatives. In HM2, a metal-binding motif has been incorporated into trastuzumab to facilitate conjugation. TrasGEX® is a glycosylation-optimized version of trastuzumab. Hertuzumab has a higher affinity for Her2 by ELISA than trastuzumab. HT-19 is an IgG1 antibody that is non-competitive with trastuzumab and pertuzumab for HER2 binding. That is, HT-19 binds to a different epitope than these two mAbs.

[0031] Many embodiments include administration of a single anti-Her2 mAb, although some embodiments include administration of multiple anti-Her2 mAbs, e.g., trastuzumab and pertuzumab. Although most of the disclosed embodiments are referred to as using an anti-Her2 mAb, additional embodiments may use an anti-Her2 polyclonal antiserum in place of the anti-Her2 mAb.

[0032] (Antibody-drug conjugates) In addition to using anti-Her2 mABs themselves as therapeutic agents, anti-Her2 mABs have also been incorporated into antibody-drug conjugates, one example being ado-trastuzumab emtansine (KADCYLA®). Additionally, A166, ALT-P7 (trastuzumab biobetter HM2 site-specifically conjugated to monomethyl auristatin E), ARX788 (HER2-targeted monoclonal antibody site-specifically conjugated to monomethyl auristatin F via the unnatural amino acid linker paraacetylphenylalanine (pAcF), DHES0815A (HER-2-targeted monoclonal antibody conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine monoamide), DS-8201a (trastuzumab deruxtecan; trastuzumab, an enzyme-cleavable maleimidoglycine glycine-phenylalanine-glycine (GGFG) peptide linker and a topoisomerase I inhibitor), fam-trastuzumab deruxtecan (ENHERTU®), RC48 (monomethyl auristatin F via a cleavable linker), Examples include the humanized anti-HER2 antibody hertuzumab conjugated to ristatin E (MMAE), SYD985 (([vic-]trastuzumab duocarmazine; trastuzumab conjugated to the synthetic duocarmycin analog secoduocarmycin hydroxybenzamide azaindole via a cleavable valine-citrulline peptide), MEDI4276 (a HER2 bispecific antibody targeting two distinct epitopes on HER2 site-specifically conjugated to AZ13599185, a potent tubulysin-based microtubule inhibitor, via a maleimidocaproyl linker), and XMT-1522 (TAK-522; HT-19 conjugated to auristatin F-hydroxypropylamide on the DOLAFLEXIN® platform).

[0033] In some embodiments, the Her2 targeting moiety comprises or is an antibody drug conjugate that comprises an anti-Her2 antibody.

[0034] (Her2 kinase inhibitor) Her2 and EGFR are closely related protein tyrosine kinases, and many drugs developed as inhibitors of one also inhibit the other. At least four drugs (lapatinib, neratinib, afatinib, and dacomitinib) that are irreversible inhibitors of these kinases are currently marketed as cancer treatments, albeit for different indications. It should be noted that not all EGFR inhibitors are irreversible inhibitors, nor are they known to cross-inhibit Her2. EGFR inhibitors that do not inhibit or are not known to inhibit Her2 do not fall under the term "Her2 inhibitors" as used in this disclosure. In some embodiments, the Her2 inhibitor is an irreversible inhibitor. In some embodiments, the Her2 inhibitor is not a reversible inhibitor.

[0035] Lapatinib (TYKERB®) (CAS No. 231277-92-2), typically provided as lapatinib ditosylate (CAS No. 388082-77-7) or its monohydrate, can be administered at 1250 or 1500 mg, depending on the indication, once daily for a 21-day treatment cycle, according to prescribing instructions, the entire contents of which are incorporated herein by reference. Lapatinib and capecitabine are administered on days 1 through 14. Lapatinib alone is administered on days 15 through 21. At the end of the 21 days, the treatment cycle is repeated unless disease progression or unacceptable toxicity occurs. Capecitabine is administered at a dose of 2000 mg / m 2 / day is given orally in two divided doses approximately 12 hours apart.

[0036] Neratinib (NERLYNX®) (CAS No. 698387-09-6) is administered at an initial dosage of 240 mg / day with food and may be administered daily for one year, according to prescribing instructions, the entirety of which are incorporated herein by reference. If toxicity exceeds Grade 1, the dosage may be reduced stepwise by 40 mg / day until toxicity is equal to or less than Grade 1. If the dosage is reduced to 120 mg / day and toxicity remains greater than Grade 1, treatment with neratinib should be discontinued.

[0037] Afatinib (GILOTRIF®) (CAS No. 850140-72-6) may be administered orally at 40 mg / day once daily without food unless disease progression occurs or the patient is unable to tolerate, according to the prescribing instructions, which are incorporated herein by reference in their entirety.

[0038] Dacomitinib (VIZIMPRO®) (CAS No. 1110813-31-4) may be administered orally at 45 mg / day once daily with or without food, in accordance with prescribing instructions, which are incorporated herein by reference, unless disease progression or unacceptable toxicity occurs, in which case the dosage may be tapered to 30 or 15 mg / day.

[0039] Tucatinib (TUKYSA®) (CAS No. 937263-43-9) may be administered orally, with or without food, at 300 mg twice daily (12 hours apart) in combination with trastuzumab and capecitabine, according to prescribing instructions, which are incorporated herein by reference, unless disease progression or unacceptable toxicity occurs. In the event of unacceptable toxicity, the dosage may be tapered in 50 mg increments to 150 mg twice daily.

[0040] The above administration information provides general instructions on the administration of these drugs, in addition to disclosing the specific embodiments in which these Her2 kinase inhibitors can be used in combination with RXR agonists.The disclosed embodiments are not necessarily limited to these specific administration regimens, and it is within the skill of a physician to modify these regimens for individual patients.The improved and synergistic effects of these drugs when used in combination with RXR agonists can achieve beneficial therapeutic effects while avoiding unacceptable toxicity from the use of low doses of kinase inhibitors.

[0041] Other Her2 kinase inhibitors include canertinib (CAS No. 267243-28-7), sapitinib (CAS No. 848942-61-0), CP-724714 (CAS No. 537705-08-1), and CUDC-101 (CAS No. 1012054-59-9).

[0042] (RXR agonist) Preclinical studies with rexinoids suggest that selective activation of the retinoid X receptor (RXR), which regulates functions related to differentiation, inhibition of cell proliferation, apoptosis, and metastasis, may be useful in treating a variety of diseases related to biochemical functions regulated by RXR.

[0043] Retinoic acid receptors (RAR) and RXR and their cognate ligands function by different mechanisms of action. The term "RAR" as used in this disclosure means one or more of RARα, RARβ or RARγ. The term "RXR" as used in this disclosure means one or more of RXRα, RXRβ or RXRγ. RAR biomarkers are characteristic biological, biochemical or biologically derived indicators that indicate RAR activity in patients. RAR biomarkers include, but are not limited to, CYP26 levels, CRBPI levels, and the like, and combinations thereof.

[0044] In some embodiments, RAR activation threshold refers to one or more of CYP26 levels increased by 25% above baseline and CRBPI levels increased by 25% above baseline. RAR forms heterodimers with RXR, and these RAR / RXR heterodimers bind to specific response elements in the promoter regions of target genes. Binding of RAR agonists to the heterodimeric RAR receptors activates the transcription of target genes and induces retinoid action. RXR agonists of the present disclosure do not activate RAR / RXR heterodimers. Because activation of transcription by ligand binding occurs only with non-RXR proteins (e.g., RAR), and not with RXR, RXR heterodimer complexes such as RAR / RXR can be referred to as non-permissive RXR heterodimers.

[0045] RXR also interacts with nuclear receptors other than RAR, and RXR agonists may induce some of their biological effects by binding to such RXR / receptor complexes. Because activation of transcription by ligand binding can occur at RXR, other receptors, or both receptors, these RXR / receptor complexes can be referred to as permissive RXR heterodimers. Examples of permissive RXR heterodimers include, but are not limited to, peroxisome proliferator-activated receptor / RXR (PPAR / RXR), farnesyl X receptor / RXR (FXR / RXR), nuclear receptor-associated 1 protein (Nurr1 / RXR), and liver X receptor / RXR (LXR / RXR). RXR can also form RXR / RXR homodimers and be activated by RXR agonists to induce rexinoid effects. RXR also interacts with proteins other than nuclear receptors, and ligand binding to RXR in such protein complexes can also induce rexinoid effects. Due to these differences in mechanism of action, RXR agonists and RAR agonists induce different biological effects, and even if they mediate similar biological effects, they do so through different mechanisms. Furthermore, the undesirable side effects of retinoids, such as proinflammatory reactions or mucocutaneous toxicity, are mediated by the activation of one or more RAR receptor subtypes. In other words, the biological effects mediated through the RXR pathway do not induce proinflammatory reactions and therefore do not result in undesirable side effects.

[0046] Thus, aspects of the present disclosure provide, in part, RXR agonists. As used in this disclosure, the term "RXR agonist" is synonymous with "selective RXR agonist" and refers to a compound that selectively binds to one or more RXR receptors, such as RXRα, RXRβ, or RXRγ, in a manner that induces gene transcription through RXR response elements. As used in this disclosure with respect to RXR agonists, the term "selectively binds" refers to an RXR agonist that does not substantially bind to non-target receptors, such as RARα, RARβ, or RARγ, and that the RXR agonist differentially binds to intended target receptors, such as RXRα, RXRβ, or RXRγ. In some embodiments, the term "RXR agonist" includes esters of RXR agonists.

[0047] For each of the disclosed embodiments, the RXR agonist can be a compound having the structure of Formula I, or a pharma- ceutically acceptable salt thereof: [ka] R is H or lower alkyl having 1 to 6 carbon atoms.

[0048] The present disclosure also discloses esters of RXR agonists. The esters may be derived from the carboxylic acid at C1, or the esters may be derived from a carboxylic acid functionality at another site on the molecule, such as the phenyl ring. Without intending to be limiting, the esters may be alkyl esters, aryl esters, or heteroaryl esters. The term "alkyl" has the meaning commonly understood by those skilled in the art and refers to a linear, branched, or cyclic alkyl moiety. C 1~6Alkyl esters are particularly useful, where the alkyl portion of the ester has 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having 1-6 carbon atoms, etc. In some embodiments, the RXR agonist is an ethyl ester of formula I.

[0049] In some embodiments, the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid, also known as IRX4204, and has the following chemical structure: [ka]

[0050] Pharmaceutically acceptable salts of RXR agonists can also be used in the disclosed embodiments. Disclosed are compounds that have sufficient acidic, sufficient basic or both functional groups, thereby reacting with any of many organic or inorganic bases and inorganic and organic acids to form salts.

[0051] Acids commonly used to form acid addition salts from RXR agonists having a basic group are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc., and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc. Examples of such salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne- These include 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0052] Bases commonly used to form base addition salts from RXR agonists having an acidic group include, for example, hydroxides of alkali metals such as sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia, and, for example, unsubstituted or hydroxy-substituted mono-, di- or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; for example, mono-, biphenylamine; Examples of the amines include, but are not limited to, mono-, bis-, or tris-(2-hydroxy lower alkylamines), for example, N,N-di-lower alkyl-N-(hydroxy lower alkyl)amines or tri-(2-hydroxyethyl)amine, such as N,N-dimethyl-N-(2-hydroxyethyl)amine; organic amines, such as N-methyl-D-glucamine; and amino acids, such as, for example, arginine and lysine.

[0053] IRX4204, like some other RXR ligands, does not activate non-permissive heterodimers such as RAR / RXR. However, IRX4204 is unique in that it specifically activates Nurr1 / RXR heterodimers and does not activate other permissive RXR heterodimers such as PPAR / RXR, FXR / RXR and LXR / RXR. Other RXR ligands generally activate these permissive RXR heterodimers. Therefore, all RXR ligands cannot be classified as belonging to one class. IRX4204 belongs to a unique class of RXR ligands that specifically activates only Nurr1 / RXR heterodimer, which is one of RXR homodimers and permissive RXR heterodimers.

[0054] In one embodiment, the selective RXR agonist does not appreciably activate the permissive heterodimers PPAR / RXR, FXR / RXR and LXR / RXR. In another embodiment, the selective RXR agonist activates the permissive heterodimer Nurr1 / RXR. One example of such a selective RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthal-7-yl]2(E),4(E)heptadienoic acid (IRX4204), the structure of which is shown in formula II. In other aspects of this embodiment, activation of the permissive heterodimers PPAR / RXR, FXR / RXR, or LXR / RXR by an RXR agonist is 1% or less, 2% or less, 3% or less, 4% or less, 5% or less, 6% or less, 7% or less, 8% or less, 9% or less, or 10% or less than the ability of a non-RXR receptor activating agonist to activate the same permissive heterodimer. Examples of RXR agonists that activate one or more of PPAR / RXR, FXR / RXR, or LXR / RXR include LGD1069 (bexarotene) and LGD268.

[0055] Binding specificity refers to the ability of an RXR agonist to discriminate between an RXR receptor and a receptor that does not contain the binding site for the RXR agonist, such as the RAR receptor.

[0056] Certain embodiments provide a method of treating cancer comprising administering to a patient in need thereof an RXR agonist at a level below the RAR activation threshold and at or above the RXR activation threshold.

[0057] About IRX4204, RAR EC 10 (effective concentration to induce 10% of the maximum activity of RAR) is 300 nM for the α isoform and 200 nM for the β and γ isoforms. Thus, in some embodiments, concentrations not exceeding 200 nM are considered to be below the RAR activation concentration. For IRX4204, the RXR EC 90(effective concentration to induce 90% of maximal activity of RXR) is 0.1 nM for the α and γ isoforms and 1 nM for the β isoform. Thus, in some embodiments, a concentration of at least 0.1 nM is considered to exceed the RXR activation threshold. Based on human studies, 20 mg / m 2 Oral doses of IRX4204 per day result in systemic concentrations that remain below 200 nM. Similarly, 0.01-0.02 mg / m 2 Oral doses in the range of 0.1 nM or more per day are estimated to result in systemic concentrations of 0.1 nM or more. Thus, in various embodiments, the dose of IRX4204 is at least 0.01, 0.02, 0.03, 0.05, 0.1, 0.3, 0.5, 1, 3 or 5 mg / m 2 / day and 150, 200 or 300 mg / m 2 / day, or a range bounded by a combination of these values.

[0058] In other embodiments, the dosage of an RXR agonist, e.g., IRX4204, for an adult human is 0.2 to 300 mg / day, and in each embodiment, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / day, but not exceeding 10, 15, 20, 50 or 100 mg / day, or a range bounded by any combination of these values.

[0059] The RXR agonist can be administered to a mammal using standard administration techniques, including parenteral, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. The term "parenteral" as used in this disclosure includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. The RXR agonist is preferably suitable for oral administration, for example as a pill, tablet, or capsule. Administration may be continuous or intermittent. In certain embodiments, the total number of daily administrations of the RXR agonist can be a single administration or two administrations in a 24-hour period, with an interval of 8 to 16 hours or 10 to 14 hours.

[0060] (Thyroid Hormones) Both biologically derived and synthetic thyroid hormones have been used in medicine. The major forms of thyroid hormones are called T3 (triiodothyronine) and T4 (thyroxine). Thyroxine is less active but has a long half-life and is sometimes considered a prohormone of triiodothyronine. As used in this disclosure, the term "thyroid hormone" refers to both thyroxine and triiodothyronine. Thyroxine (thyroid hormone T4, levothyroxine sodium) is a tyrosine-based hormone produced by the thyroid gland and is primarily involved in regulating metabolism. Both are widely commercially available and suitable for use in the embodiments of the present disclosure. However, levothyroxine, a synthetic form of T4, is much more commonly utilized in clinical practice (except for patients who cannot convert T4 to T3) because its long half-life in the body facilitates once-daily administration. In some embodiments, the thyroid hormone administered is specifically thyroxine. In some embodiments, the thyroid hormone administered is triiodothyronine.

[0061] Administration of RXR agonists or their esters can result in suppression of serum thyroid hormones, potentially resulting in clinical hypothyroidism and associated disorders. However, in some embodiments, thyroid hormones are not co-administered (or are not co-administered initially) to improve suppression of serum thyroid hormone levels. Co-administration of thyroid hormones and RXR agonists improves the anti-cancer effects of RXR agonists, possibly through multiple mechanisms of action, compared to the effects of RXR agonists alone. Co-administered thyroid hormones can also reduce the hypothyroidism-inducing effects of RXR agonists, thereby improving the clinical safety and tolerability of the treatment. Thus, in preferred embodiments, thyroid hormones are co-administered with RXR agonists to enhance the effects of the treatment, regardless of whether administration of the RXR agonist has caused or is expected to cause clinical hypothyroidism. Administering thyroid hormones in concert or in combination with RXR agonists means that the respective administration methods of these two drugs are such that the physiological effects of the two drugs overlap in time. This does not require that the RXR agonist and the thyroid hormone be contained in the same composition or formulation, or be administered as separate compositions at the same time, by the same route of administration, or on the same schedule, although in some embodiments they may be any of the foregoing.

[0062] Suitable thyroxine dosages are generally from about 5 μg / day to about 250 μg / day administered orally initially, with the dosage increased every 2-4 weeks as needed. In other embodiments, suitable thyroxine dosages are from about 5 μg / day to about 225 μg / day, from about 7.5 μg / day to about 200 μg / day, from about 10 μg / day to about 175 μg / day, from about 12.5 μg / day to about 150 μg / day, from about 15 μg / day to 125 μg / day, from about 17.5 μg / day to about 100 μg / day, from about 20 μg / day to about 100 μg / day, or from about 20 μg / day to about 100 μg / day. μg / day, about 22.5 to about 100 μg / day, about 25 μg / day to about 100 μg / day, about 5 μg / day to about 200 μg / day, about 5 μg / day to about 100 μg / day, about 7.5 μg / day to about 90 μg / day, about 10 μg / day to about 80 μg / day, about 12.5 μg / day to about 60 μg / day, about 15 μg / day to about 50 μg / day. Dosage escalation is generally at about 5 μg / day, about 7.5 μg / day, about 10 μg / day, about 12.5 μg / day, about 15 μg / day, about 20 μg / day, or about 25 μg / day. In certain embodiments, an appropriate thyroid hormone dosage is one that produces a serum level of T4 in the upper 50%, upper 60%, upper 70%, upper 80%, or upper 90% of the normal range within a laboratory. Normal ranges for T4 levels may vary by laboratory, and target T4 levels are based on the normal range determined for each particular laboratory.

[0063] For each embodiment including a combination of an RXR agonist and a Her2 targeted therapeutic, there are analogous embodiments in which such combination further includes thyroid hormone.

[0064] Pharmaceutical Compositions and Formulations The various active pharmaceutical ingredients used in the treatment described in this disclosure are typically present as pharmaceutical compositions or formulations. Such compositions or formulations may be liquid, semi-solid or solid formulations. The formulations of this disclosure may be prepared in a manner that forms one phase, such as an oil or a solid. Alternatively, the formulations of this disclosure may be prepared in a manner that forms two phases, such as an emulsion. The pharmaceutical compositions of this disclosure intended for such administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0065] Liquid preparations suitable for parenteral injection or nasal spray may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Preparations suitable for nasal administration may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol (PEG), glycerol, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0066] The pharmaceutical compositions of the present disclosure may optionally include a pharma- ceutically acceptable carrier that facilitates processing of the active compound into a pharma- ceutically acceptable composition. As used in this disclosure, the term "pharmaceutically acceptable" means a compound, material, composition and / or dosage form that, within the scope of sound medical judgment, is suitable for contact with human and animal tissues without undue toxicity, irritation, allergic response or other problem complications commensurate with a reasonable benefit / risk ratio. This definition also applies to the phrase "pharmaceutically acceptable salts thereof". As used in this disclosure, the term "pharmaceutically acceptable carrier" is synonymous with "pharmaceutical carrier" and refers to any carrier that produces substantially no long-term or permanent adverse effects when administered, and includes terms such as pharma- ceutical acceptable vehicles, stabilizers, diluents, additives, adjuvants or excipients. Such carriers are generally acceptable for mixing with, diluting or encapsulating the active compound, and may be solid, semi-solid or liquid medicines. It is understood that the active compound may be soluble or may be delivered as a suspension in the desired carrier or diluent. Any of a variety of pharma- ceutically acceptable carriers can be used, including, but not limited to, aqueous media such as water, saline, glycine, hyaluronic acid, and the like; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talc, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; and any other inactive ingredients. The choice of pharma-ceutically acceptable carrier can depend on the mode of administration. Except where a pharma-ceutically acceptable carrier is incompatible with the active compound, its use in a pharma-ceutically acceptable composition is contemplated. Non-limiting examples of the specific uses of such pharmaceutical carriers include those described in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al. eds, Lippincott Williams & Wilkins Publishers, 7 thed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20 th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al. eds, McGraw-Hill Professional, 10 th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4 th These protocols are prescribed and any modifications are within the scope of those skilled in the art and well within the scope of the teachings of this disclosure.

[0067] The pharmaceutical compositions of the present disclosure may optionally contain other pharma- ceutically acceptable ingredients (or pharmaceutical components), including, but not limited to, buffers, preservatives, isotonicity agents, salts, antioxidants, osmolality adjusters, bioactive substances, pharmacologically active substances, bulking agents, emulsifiers, wetting agents, sweeteners or flavoring agents, and the like. Various buffers and pH adjustment methods can be used in the preparation of the pharmaceutical compositions of the present disclosure, provided that the resulting preparation is pharma- ceutically acceptable. Such buffers include, but are not limited to, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline, and phosphate buffered saline. It is understood that acids or bases can be used to adjust the pH of the composition, as needed. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium disulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stabilized oxychloro compositions such as, for example, sodium chlorite, and chelating agents such as, for example, DTPA or DTPA-bisamide, calcium DTPA and CaNaDTPA-bisamide. Isotonicity agents useful in the pharmaceutical compositions include, but are not limited to, salts such as, for example, sodium chloride, potassium chloride, mannitol or glycerin, and other pharma- ceutically acceptable isotonicity agents. The pharmaceutical compositions may be provided as salts, and can be formed with many acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. It is understood that these and other materials known in the pharmaceutical arts can be included in the pharmaceutical compositions useful in the present invention.

[0068] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators.

[0069] Semi-solid formulations suitable for topical administration include, but are not limited to, ointments, creams, salves and gels. In such solid formulations, the active compound may be mixed with at least one inert conventional excipient (or carrier), such as lipids and / or polyethylene glycol.

[0070] Solid formulations suitable for oral administration include capsules, tablets, pills, powders, and granules. In such solid formulations, the active compound may be admixed with at least one inert conventional excipient (or carrier) such as sodium citrate or dicalcium phosphate or the like or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retardants, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0071] The small molecule components of various embodiments, i.e., RXR agonists, thyroid hormones and Her2 kinase inhibitors, can be formulated into solid oral dosage forms. Antibody components are generally formulated as liquids, typically for intravenous infusion. In other embodiments, antibody components may be provided in lyophilized form for reconstitution as liquid locally at the treatment site, typically intravenously infused into the patient. Although intravenous infusion is typical, in other embodiments, antibodies may be administered by other routes of administration, such as subcutaneous injection or infusion.

[0072] (treatment) The terms "treatment", "treating" and the like as used in this disclosure refer to obtaining a desired pharmacological and / or physiological effect. This may be directly observed as a slowdown in tumor growth, a stable or partial or complete response (i.e., tumor shrinkage or tumor elimination), or an increase in overall or disease-free survival. Treatment may also be observed as an improvement or alleviation of symptoms associated with the underlying cancer. However, as a cancer treatment, the purpose and mechanism of action of the disclosed embodiments is targeted to inhibit, stabilize or reduce tumor growth (including tumor metastasis), or to partially or completely eliminate the tumor, or to increase overall or disease-free survival, with effects on other cancer symptoms being secondary. Such direct treatment of other symptoms (e.g., pain, nausea, loss of appetite, etc.) is not within the scope of cancer treatment as used in this disclosure. That is, treating a cancer patient's symptoms, e.g., cachexia, is not treating the cancer. However, agents that treat cancer (e.g., affect cancer growth and / or metastasis) may also improve symptoms such as cachexia, either indirectly through their effects on cancer, or directly through pleiotropic effects. A "therapeutically effective amount" refers to an amount effective to obtain the desired therapeutic result, at the dosage and duration required. The therapeutically effective amount may vary depending on factors such as disease state, age, sex, weight, and the ability of the Her2 targeted therapeutic, RXR agonist, and thyroid hormone, if used, to elicit the desired response in an individual.

[0073] However, the dosage administered to a mammal, particularly a human, in the context of the present method should be sufficient to effect therapeutic response in the mammal within a reasonable time frame.Those skilled in the art will recognize that the exact dosage and composition and the selection of the most suitable delivery regimen are also influenced by, among other things, the pharmacological properties of the formulation, the nature and severity of the disease being treated and the physical condition and mental acuity of the patient, and the potency of the specific compound, the age, disease, weight, sex and response of the patient being treated and the stage / severity of the disease.

[0074] Therapeutic activities include administration of the pharmaceuticals, dosage forms and pharmaceutical compositions described herein to a patient, whether by a medical professional, the patient himself or any other person, particularly in accordance with the various treatment methods described herein. Therapeutic activities include orders, instructions and advice from medical practitioners, such as physicians, physician assistants, nurses, etc., which are then carried out by any other person, including other medical practitioners or the patient himself. In some embodiments, therapeutic activities may also include recommending, inducing or mandating that a particular pharmaceutical or combination of pharmaceuticals be selected for the treatment of a disease and that the pharmaceuticals are actually used, such as by insurance companies or pharmacy benefit management companies, approving coverage for a pharmaceutical, denying coverage for an alternative pharmaceutical, including a pharmaceutical in an adopted formulary or excluding an alternative pharmaceutical, or providing financial incentives to use a pharmaceutical. In some embodiments, therapeutic activities may also include recommending, inducing or mandating that a particular pharmaceutical is selected for the treatment of a disease and that the pharmaceuticals are actually used, such as by policies or practice standards, such as those established by hospitals, clinics, health maintenance organizations, medical practices or physician groups.

[0075] To benefit from the combined effects of an RXR agonist of formula I (or a pharma- ceutically acceptable salt or ester thereof) and a Her2 targeted therapeutic, embodiments include + The present invention includes a method of treating a patient with cancer, the method comprising or consisting of administering an RXR agonist of formula I (or a pharma- ceutically acceptable salt thereof) and a Her2-targeted therapeutic agent. Some embodiments further comprise administering thyroid hormone in coordination with the administration of the RXR agonist. In some embodiments, Her2 + Cancer is Her2 + In some embodiments, the cancer is Her2 + Cancer is Her2 +Gastroesophageal cancer, ovarian cancer, gastric cancer, lung adenocarcinoma, uterine cancer (such as serous endometrial cancer), or salivary duct cancer. Some embodiments specifically include one or more of these cancers. Other embodiments specifically exclude one or more of these cancers.

[0076] In various embodiments, the therapeutic methods of the present disclosure may be applied as a primary treatment, as a debulking therapy prior to surgical removal of the tumor, or as an adjuvant therapy following any form of primary treatment (particularly surgery) to address residual disease and / or reduce the risk of cancer recurrence.

[0077] In some embodiments, Her2 + The patient with cancer has not been previously treated with either an RXR agonist of formula I (or a pharma- ceutically acceptable salt thereof) or a Her2 targeted therapeutic agent. In some embodiments, the patient has been previously treated with an RXR agonist of formula I (or a pharma- ceutically acceptable salt thereof) and has achieved stable disease or a partial response (in some embodiments, as defined by RECIST or iRECIST criteria), i.e., the cancer is sensitive to an RXR agonist of formula I (or a pharma- ceutically acceptable salt thereof), and the Her2 targeted therapeutic agent is added to the treatment regimen. In some embodiments, the patient has been previously treated with a Her2 targeted therapeutic agent and has achieved stable disease or a partial response (in some embodiments, as defined by RECIST or iRECIST criteria), i.e., the cancer is sensitive to an RXR agonist of formula I (or a pharma- ceutically acceptable salt thereof), and the Her2 targeted therapeutic agent is added to the treatment regimen.

[0078] Thus, some embodiments provide methods for treating Her2-targeted disease, including treating patients with Her2-targeted disease who have received, are receiving, or will receive a Her2-targeted therapy. +The present invention includes administering RXR agonist to the patient with tumor. Some embodiments include administering RXR agonist to the patient who has had some therapeutic effect (less than complete response) with Her2 targeting therapeutic agent, i.e., administering RXR agonist is added to the treatment regimen of Her2 targeting therapeutic agent. Some embodiments include administering Her2 targeting therapeutic agent to the patient who has had some therapeutic effect (less than complete response) with RXR agonist (or RXR agonist in combination with thyroid hormone), i.e., administering Her2 targeting therapeutic agent is added to the treatment regimen of RXR agonist.

[0079] The effectiveness of treatment can be monitored by periodic evaluation of the treated patient. For repeated administration over a period of several days or more, treatment can be repeated until the desired suppression of disease or condition occurs. However, other administration regimes may be useful and are within the scope of this disclosure. Antibodies typically have a much longer half-life in the body than other active agents used in these methods, and therefore the interval between administrations is typically much longer (weeks).

[0080] The effectiveness of cancer treatments is usually measured in terms of "response." Techniques to monitor response can be similar to tests used to diagnose cancer, including, but not limited to: Lumps or tumors involving lymph nodes can be seen and evaluated externally during a medical exam. Some internal cancer tumors can be seen with an x-ray or CT scan and measured with a ruler. Blood tests, including measurements of organ function, may be performed. For certain cancers, tumor marker tests may be performed.

[0081] Regardless of the test used -- blood tests, cell counts, or tumor marker tests -- it is repeated at specific intervals so that results can be compared with previous tests of the same type.

[0082] Response to cancer treatment is defined in several ways. Complete Response: All of the cancer or tumor has disappeared and you are living without disease. Tumor marker levels (if applicable) may remain within normal ranges. Partial Response: The cancer has shrunk by some percentage, but disease remains. Tumor marker (if applicable) levels may have decreased (or increased, based on the tumor marker, as a sign of decreased tumor burden), but evidence of disease remains. Stable disease: The cancer is not growing or shrinking, there is no change in the disease, and there is no significant change in tumor markers (if applicable). Progression: The cancer is growing and the disease is worse than before treatment. Tumor marker testing (if applicable) shows an increase in tumor markers.

[0083] Other endpoints of efficacy of cancer treatment include the intervals of overall survival (i.e., the time from diagnosis or initiation of evaluated treatment to death from any cause), cancer-free survival (i.e., the period following a complete response during which no cancer is detectable), and progression-free survival (i.e., the period following stable disease or partial response during which no recurrence of tumor growth is detectable).

[0084] There are two standard methods for evaluating the efficacy of treatment of solid cancers in terms of tumor size (tumor burden): the WHO criteria and the RECIST criteria. These methods involve measuring solid tumors and modifying treatment regimens to compare current tumors with past measurements or to compare changes with future measurements. In the WHO method, the long and short axes of solid tumors are measured and their products are calculated. If there are multiple solid tumors, the sum of all products is calculated. In the RECIST method, only the long axis is measured. If there are multiple solid tumors, the sum of all long axis measurements is calculated. However, for lymph nodes, the short axis is measured instead of the long axis. There is also a RECIST method for immunotherapy (iRECIST), which takes into account the unique behavior associated with this type of therapeutic agent, such as delayed response after pseudo-progression. Both the RECIST 1.1 guideline and the iRECIST guideline are incorporated by reference in their entirety into this disclosure.

[0085] In some embodiments of the methods of the present disclosure, the tumor burden in a treated patient is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or a range bounded by these values.

[0086] In other embodiments, the one-year survival rate of treated subjects is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or a range bounded by these values.

[0087] In other embodiments, the 5-year survival rate of treated subjects is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or a range bounded by these values.

[0088] In other embodiments, the 10-year survival rate of treated subjects is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100%, or a range bounded by these values.

[0089] In still other embodiments, the subject has sustained remission for at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 22 months, at least 24 months, at least 27 months, at least 30 months, at least 33 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, or at least 60 months or more.

[0090] In other embodiments, the method can additionally help treat or alleviate cancer-related diseases, conditions or disorders.In some embodiments, these diseases or conditions include, but are not limited to, anemia, asthenia, cachexia, Cushing's syndrome, fatigue, gout, periodontal disease, hematuria, hypercalcemia, hypothyroidism, internal bleeding, hair loss, mesothelioma, nausea, night sweats, neutropenia, paraneoplastic syndrome, pleurisy, polymyalgia rheumatica, rhabdomyolysis, stress, lymphadenopathy, thrombocytopenia, vitamin D deficiency or weight loss.Cancer treatment can alleviate or treat associated conditions, but treating cancer-related conditions is not cancer treatment if tumors are not expected to shrink or disappear or to inhibit tumor growth or expansion.

[0091] Toxicity and adverse events are often graded on a five-point scale. Grade 1 or mild toxicity induces no symptoms or only mild symptoms; can be characterized by only clinical or diagnostic observations; and no therapeutic intervention is indicated. Grade 2 or moderate toxicity may impair activities of daily living (e.g., food preparation, shopping, money management, phone use), but only minimal, localized, or non-invasive therapeutic intervention is indicated. Grade 3 toxicity is medically significant but not immediately life-threatening; hospitalization or extended hospitalization is indicated and may impair activities of daily living related to self-care (e.g., bathing, dressing, eating, toileting, taking medication, and avoiding bedriddenness). Grade 4 toxicity is life-threatening and emergency therapeutic intervention is indicated. Grade 5 toxicity results in death associated with the adverse event. Thus, in various embodiments, the use of an RXR agonist or an RXR agonist and thyroid hormone reduces the grade of toxicity associated with the use of Her2-targeted therapy by allowing the use of lower doses without substantially sacrificing efficacy. In some embodiments, the use of an RXR agonist or an RXR agonist and thyroid hormone in combination with a Her2 targeted therapy reduces toxicity to Grade 1 or below or produces no toxicity findings without a substantial decrease in efficacy as would be expected from a Her2 targeted therapy alone. In some embodiments, the combination of a Her2 targeted therapy and an RXR agonist or an RXR agonist and thyroid hormone allows for continued use of a Her2 targeted therapy at a therapeutically effective low dose in cases where treatment with a Her2 targeted therapy would have to be discontinued due to unacceptable toxicity. In some of these embodiments, the Her2 targeted therapy comprises a Her2 kinase inhibitor.

[0092] The combination of the disclosed RXR agonist and Her2 targeted therapeutic agent produces synergistic effects. That is, they interact in a positive manner that produces greater inhibition of tumor cell growth than would be expected from the independent (non-interactive) effects of both. Thus, some embodiments produce improved efficacy. Other embodiments allow for reduced dosage to reduce toxicity while still achieving at least similar efficacy as provided by individual therapeutic agents. In some embodiments, both reduced toxicity and improved efficacy (compared to more toxic single agents) are achieved.

[0093] For each treatment, Her2 + Use of an RXR agonist in combination with a Her2 targeted therapy or a Her2 targeted therapy and thyroid hormone to treat cancer; Her2 + Further similar embodiments exist for the aforementioned methods directed to the use of an RXR agonist in the manufacture of a medicament for use in combination with a Her2 targeted therapeutic or a Her2 targeted therapeutic and thyroid hormone to treat cancer.

[0094] Further embodiments include combinations comprising an RXR agonist and a Her2 targeted therapeutic agent as detailed in this disclosure. Some embodiments further comprise a thyroid hormone. In some embodiments, the Her2 targeted therapeutic agent is an anti-Her2 antibody. In some embodiments, the Her2 targeted therapeutic agent is a Her2 kinase inhibitor.

[0095] Further embodiments include kits containing the above combinations. The kits may further include solvents, diluents, injectors, etc. that may facilitate administration of one or more therapeutic agents. The kits may further include instructions for the coordinated use of the therapeutic agents utilized in the disclosed methods, regardless of whether any particular agent is provided in the kit.

[0096] List of Specific Embodiments The following list of embodiments is illustrative of the various embodiments, with respect to scope, combinations and subcombinations, classifications of inventions, etc., described in this disclosure, but is not intended to be an exhaustive recitation of all embodiments supported by this disclosure.

[0097] Embodiment 1. A method for treating Her2-targeted therapeutic drug-resistant Her2 comprising administering to a patient an RXR agonist of formula I or a pharma- ceutical acceptable salt thereof. + 1. A method of treating a patient with cancer, comprising: [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms. Patients must have received, are receiving, or will receive a Her2-targeted therapy; method.

[0098] Embodiment 2. A method for treating Her2 targeted therapy-resistant Her2 comprising administering an RXR agonist of formula I or a pharma- ceutical acceptable salt thereof and a Her2 targeted therapy. + 1. A method of treating a patient with cancer, comprising: [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms. method.

[0099] Embodiment 3. A Her2 patient undergoing treatment with an RXR agonist of formula I or a pharma- ceutical acceptable salt thereof. + A method of treating a patient with cancer, the cancer having become resistant to an RXR agonist, comprising continuing treatment with an RXR agonist and initiating treatment with a Her2 targeted therapy; [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms. method.

[0100] Embodiment 4. Her2 patients receiving treatment with a Her2 targeted therapy + A method of treating a patient with cancer, the cancer having become resistant to a Her2 targeted therapy, comprising continuing treatment with the Her2 targeted therapy and initiating treatment with an RXR agonist of formula I, or a pharma- ceutical acceptable salt thereof; [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms. method.

[0101] Embodiment 5. A method for treating Her2-targeted therapeutic drug-resistant Her2 comprising administering to a patient an RXR agonist of formula I or a pharma- ceutical acceptable salt thereof. + 1. A method of treating a patient with cancer, comprising: [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms. Patients must have received, are receiving, or will receive Her2-targeted therapy; method.

[0102] Embodiment 6. The Her2 targeted therapy comprises: Her2 + Methods for inhibiting tumor cell proliferation, Her2 + Methods for mediating ADCC of tumor cells, Immunoglobulin method to inhibit Her2 signaling Her2 + A method for delivering a cytotoxic agent to a cell; or Small molecule methods to inhibit Her2 kinase activity, 6. The method of embodiment 5, wherein

[0103] Embodiment 7. A method for activating a RXR / Nurr1 heterodimer receptor or a rexinoid method for inhibiting tumor growth, comprising administering to a patient a Her2-targeted therapeutic drug-resistant Her2 tumor. +A method of treating a cancer patient, wherein the patient has received, is receiving, or will receive a Her2 targeted therapy.

[0104] Embodiment 8. The method of any one of embodiments 1-7, further comprising administering a thyroid hormone in combination with the RXR agonist.

[0105] Embodiment 9. The method of embodiment 8, wherein the thyroid hormone is thyroxine.

[0106] Embodiment 10. The method of any one of embodiments 1-9, wherein the RXR agonist, method of activating the RXR / Nurr1 heterodimer receptor or rexinoid method of inhibiting tumor growth is a compound of formula I.

[0107] Embodiment 11. The method of any one of embodiments 1-9, wherein the RXR agonist, method of activating the RXR / Nurr1 heterodimer receptor or rexinoid method of inhibiting tumor growth is a pharma- ceutically acceptable salt of a compound of formula I.

[0108] Embodiment 12. The method of any one of embodiments 1-9, wherein the RXR agonist, method of activating the RXR / Nurr1 heterodimer receptor or rexinoid method of inhibiting tumor growth is a compound of formula II. [ka]

[0109] Embodiment 13. The method according to any one of embodiments 1 to 12, Her2 targeted therapy, Her2 + Methods for inhibiting tumor cell proliferation, Her2 + Methods for mediating ADCC of tumor cells, Immunoglobulin methods that block Her2 signaling, or Her2 + A method for delivering a cytotoxic agent to a cell, including anti-Her2 therapeutic antibodies, method.

[0110] Embodiment 14. The method of embodiment 13, wherein the therapeutic antibody is trastuzumab or pertuzumab.

[0111] Embodiment 15. The method of embodiment 13, wherein the therapeutic antibody is margetuximab, TrasGEX, HM2, hertuzumab or HT-19.

[0112] Embodiment 16. Her2 targeted therapeutic agent, Her2 + The method according to any one of embodiments 1 to 13, wherein the method of inhibiting tumor cell proliferation or the immunoglobulin method of inhibiting Her2 signaling comprises an antibody drug conjugate, and the antibody is an anti-Her2 antibody.

[0113] Embodiment 17. Antibody drug conjugate or Her2 + 17. The method of embodiment 16, wherein the method for delivering a cytotoxic agent to a cell is ado-trastuzumab emtansine.

[0114] Embodiment 18. Antibody drug conjugate or Her2 + 17. The method of embodiment 16, wherein the method of delivering a cytotoxic agent to a cell is A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 or XMT-1522.

[0115] Embodiment 19. The method of any one of embodiments 1-12, wherein the Her2 targeted therapeutic or small molecule method that inhibits Her2 kinase activity comprises a Her2 kinase inhibitor.

[0116] Embodiment 20 The method of embodiment 19, wherein the Her2 kinase inhibitor is lapatinib or neratinib.

[0117] Embodiment 21 The method of embodiment 19, wherein the Her2 kinase inhibitor is afatinib or dacomitinib.

[0118] Embodiment 22. The method of any one of embodiments 1 to 21, wherein the treatment is by weight loss therapy.

[0119] Embodiment 23. The method of any one of embodiments 1 to 21, wherein the treatment is by adjunctive therapy.

[0120] Embodiment 24. Her2 + Cancer is Her2 + The method of any one of embodiments 1 to 23, wherein the cancer is breast cancer.

[0121] Embodiment 25. Her2 + Cancer, Her2 + The method of any one of embodiments 1 to 23, wherein the cancer is gastroesophageal cancer, ovarian cancer, gastric cancer, lung adenocarcinoma, uterine cancer (such as serous endometrial cancer) or salivary duct cancer.

[0122] Embodiment 26 The method of any one of embodiments 1-25, wherein the therapeutic response to the RXR agonist and Her2 targeted therapeutic agent is greater than the response to either agent alone.

[0123] Embodiment 27. The method of embodiment 26, wherein the greater therapeutic response is a slowing of tumor growth, stable disease, a partial response, a complete response, an increase in overall survival or disease-free survival.

[0124] Embodiment 28. The method of embodiment 26 or 27, wherein the response is assessed according to RECIST or iRECIST criteria.

[0125] Embodiment 29. The method of any one of embodiments 26-28, comprising reducing or ameliorating secondary symptoms.

[0126] Embodiment 30. Her2 Targeted Therapy Resistant Her2 + The method of any one of embodiments 26-29, wherein the cancer is also resistant to an RXR agonist.

[0127] Embodiment 31. An RXR agonist of formula I or a pharma- ceutically acceptable salt thereof, [ka] R is H or lower alkyl having 1 to 6 carbon atoms; Her2-targeted drug-resistant Her2 in patients who have received, are receiving, or will receive Her2-targeted drugs + Used in the manufacture of medicines to treat cancer, RXR agonist.

[0128] Embodiment 32. Her2 + 2. An RXR agonist of formula I, or a pharma- ceutically acceptable salt thereof, and a Her2 targeted therapeutic agent for use in the manufacture of a medicament for use in combination to treat cancer. [ka] In this formula, R is H or lower alkyl having 1 to 6 carbon atoms.

[0129] Embodiment 33. Her2 + Her2-targeted drug-resistant Her2 in cancer patients + 2. An RXR agonist of formula I, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms. Combined with Her2 targeted therapy, RXR agonist.

[0130] It is apparent that each of the embodiments or embodiments 31-33 can be modified in a similar manner to the modification of embodiments 1-5 and 7 by embodiments 5 and 8-29.

[0131] (Example) The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of representative embodiments presently contemplated, and should not be construed as limiting any of the embodiments described in this disclosure.

[0132] Example 1 Inhibitory effect of IRX4204 and trastuzumab in combination with breast cancer cell proliferation Two breast cancer cell lines, MCF7 and SkBr3, were cultured in the presence of 0, 10, 100 or 1000 nM IRX4204 and 0, 0.1, 1 or 10 μg / ml trastuzumab. MCF7 was cultured in the presence of ER + PR + Her2 - The cell line SkBr3 is an ER - PR - Her2 + Cell lines. Cells were plated in 96-well optical plates and IRX-4204 and trastuzumab were added 24 hours after cell plating. After an additional 6 days, cells were fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS). Nuclei were stained with DAPI and imaged with a MetaXpress® microscope (Molecular Devices, San Jose, CA). Cell nuclei were segmented and counted using algorithms in the MetaXpress® image analysis software by setting the size of interest and pixel intensity relative to the background. Experimental data points were performed a minimum of four times and results are reported as the mean cell number ± standard deviation (SD). As shown in Figure 1A, both drugs individually suppressed the proliferation and proliferation of Her2 - As shown in Figure 1B, neither drug individually inhibited Her2 + They had a mild growth inhibitory effect on the SkBr3 cell line, and when used in combination, had a very large growth inhibitory effect, even at the lowest concentration tested.

[0133] To assess whether this improved growth inhibition effect was synergistic, the percent inhibition observed at the highest concentration of the combined therapeutics was compared to the percent inhibition expected for the combination based on the observed inhibition of the therapeutics used alone when the therapeutics acted independently, i.e., without interaction (see Table 1): PAE=(FE1+((1-FE1)×FE2))×100, where PAE is the predicted additive effect, FE1 is the fractional effect observed for the first treatment, and FE2 is the fractional effect observed for the second treatment. [Table 1]

[0134] The combined inhibitory effect of IRX4204 and trastuzumab would be predicted to be 68.5% if there was no interaction between the effects of the two drugs; however, the actual inhibition observed was 88.7%, clearly demonstrating that IRX4204 and trastuzumab act synergistically.

[0135] Example 2 Inhibitory effect of IRX4204 and lapatinib or neratinib in combination on breast cancer cell proliferation The experiment of Example 1 was repeated using the Her2 kinase inhibitors lapatinib or neratinib at 0, 0.1, 1 or 10 nM instead of trastuzumab. In addition, the panel of breast cancer cell lines was expanded to include ER + PR + Her2 + Cell lines BT474 and ER + PR - Her2 + The cell line MDA-MB-361 was also included. Her2 - MCF7 cell lines generally showed modest responses to treatment, and Herceptin + The general pattern seen above was again observed, with cell lines showing greater inhibition to the combination than to either agent alone (see Figures 2 and 3).

[0136] To assess whether this improved growth inhibitory effect was synergistic, the percent inhibition observed at the highest concentration of the combined therapeutics was compared to the percent inhibition expected for the combination based on the observed inhibition of the therapeutics used alone when the therapeutics acted independently, i.e., without interaction (see Tables 2-4). [Table 2] [Table 3] [Table 4]

[0137] Although in some cases the individual therapeutic agents were highly effective alone, leaving little room for synergy to be observed, in all cases the degree of inhibition observed was greater than would be expected in the absence of an interaction between the effects of the two agents. These data also clearly demonstrate that IRX4204 and a small molecule Her2 kinase inhibitor interact synergistically.

[0138] Example 3 Her2 targeting drug resistant Her2 + Inhibition of cancer cell line proliferation HCC1954 is a Her2-positive breast cancer + HCC1954 is a cancer cell line. Compared with the SkBr3 cell line used in Example 1 above, HCC1954 is resistant to neratinib, lapatinib and tucatinib. HCC1954 is also resistant to anti-Her2 monoclonal antibodies such as trastuzumab. In addition, HCC1954 is highly resistant to IRX4204. Among the Her2-amplified cell lines, HCC1954 is the most resistant to neratinib with IC50>100nM (compared to 7nM for SkBr3 or 20nM for AU565).

[0139] HCC1954 human breast cancer cells were seeded at 3000 cells per well in 96-well plates and treated with neratinib [1 or 10 nM] or DMSO (0.1%) in combination with IRX4204 [10, 100, or 1000 nM]. After 6 days of treatment, cells were fixed with 4% paraformaldehyde. Nuclei were stained with DAPI, imaged using ImageXpress® Pico (Molecular Devices), and counted with CellReporterXpress® analysis software. (Figure 4A-B) Each data point represents six replicates. Statistical significance was determined using the Bonferroni-Dunn method of multiple t-test. Each day was analyzed separately without assuming a constant SD (*p<0.01). IRX4204 showed no growth inhibitory effect on this cell line as a single agent, so the improved inhibition when used in combination with neratinib is a clear synergistic effect.

[0140] Experiments were also performed using tucatinib or lapatinib instead of neratinib. Tucatinib has an IC50>2 μM in HCC1954 compared to 22 nM for SkBr3 or 125 nM for AU565. Lapatinib has an IC50>1.4 μM in HCC1954 compared to 152 nM for SkBr3 or 294 nM for AU565. A general pattern of inhibitory effects similar to that of neratinib is observed. Specifically, IRX4204 had no growth inhibitory effect on this resistant cell line, whereas kinase inhibitors had a modest but not significant effect at the higher concentrations tested, and the combination of an RXR agonist and a Her2 kinase inhibitor had a significant growth inhibitory effect (Figure 5A-B). As with neratinib, there is clear synergy in the combination of IRX4204 with these kinase inhibitors.

[0141] Although the structures of these three kinase inhibitors share some common elements, they are not closely structurally analogous, and therefore the synergistic effects observed between these three kinase inhibitors and IRX4204 support the generality of the effects for Her2 kinase inhibitors.

[0142] Finally, although aspects of the present disclosure are highlighted by reference to specific embodiments, those skilled in the art will readily appreciate that these disclosed embodiments are merely illustrative of the principles of the subject matter of the present disclosure. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methodology, protocols and / or reagents, etc. described in the present disclosure. Thus, various modifications or configuration changes or substitutions of the disclosed subject matter can be made in accordance with the teachings of the present disclosure without departing from the spirit of the present disclosure. Finally, the terms used in the present disclosure are for the purpose of describing specific embodiments only, and are not intended to limit the scope of the present invention, which is defined solely by the claims. Thus, the present invention is not limited to what has been precisely shown and described.

[0143] Certain embodiments of the present invention have been described in this disclosure, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect that such variations will be adopted by those skilled in the art as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described in this disclosure. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended to this disclosure as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the present invention unless otherwise indicated in this disclosure or clearly contradicted by context.

[0144] Groupings of alternative embodiments, elements or steps of the invention are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other group members disclosed in this disclosure. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusions or deletions are made, the present disclosure will be deemed to include the modified group and therefore will satisfy all Markush group recitations used in the appended claims.

[0145] Unless otherwise indicated, all numerical values ​​expressing properties, items, quantities, parameters, characteristics, terms, etc. used in the present disclosure and claims shall be understood in all instances to be modified by the term "about". When used in this disclosure, the term "about" means that the property, item, quantity, parameter, characteristic or term so modified encompasses a range of plus or minus 10 percent above or below the value of the stated property, item, quantity, parameter, characteristic or term. Thus, unless indicated to the contrary, the numerical parameters set forth in this disclosure and the appended claims are approximations that may vary. At the very least, and without intending to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed, at the very least, in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains certain errors necessarily resulting from the standard deviation found in each testing measurement. The recitation of numerical ranges in this disclosure is merely intended to serve as a shorthand method of referring individually to each separate value falling within that range. Unless otherwise indicated in the disclosure, each separate value in a numerical range is incorporated into this disclosure as if it were individually set forth in the disclosure.

[0146] The terms "a," "an," "the," and similar reference words used in the context of describing the present invention (particularly in the context of the claims below) shall be construed to encompass both the singular and the plural, unless otherwise indicated in the disclosure or clearly contradicted by context. All methods described in this disclosure can be performed in any suitable order, unless otherwise indicated in the disclosure or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided in this disclosure is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention as otherwise claimed. No language in this disclosure should be construed as indicating any non-claimed element essential to the practice of the invention.

[0147] Certain embodiments disclosed in this disclosure may be further limited in the claims using the phrase "consisting of" or "consisting essentially of." When used in the claims, whether as filed or added by amendment, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to those materials or steps specified and which do not materially affect the basic and novel characteristic(s). The embodiments of the invention so claimed are essentially or explicitly described and embodied in this disclosure.

[0148] All patents, patent publications and other publications referenced or identified in this disclosure are individually and expressly incorporated by reference in their entirety into this disclosure, for example, for the purpose of describing and disclosing the compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents.

[0149] [Note] [Appendix 1] Her2 resistant to at least one Her2-targeted drug + 1. A method of treating a patient with cancer, comprising: administering to said patient a retinoid X receptor (RXR) agonist of formula I or a pharma- ceutically acceptable salt thereof; [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms; The patient has been or is currently receiving the Her2 targeted therapy. method.

[0150] [Appendix 2] 2. The method of claim 1, further comprising administering the Her2 targeted therapy.

[0151] [Appendix 3] Her2 receiving treatment with Her2-targeted drugs + 1. A method of treating a patient with cancer, comprising: the cancer has become resistant to the Her2 targeted therapy, the method comprising continuing treatment with the Her2 targeted therapy and initiating treatment with an RXR agonist of formula I, or a pharma- ceutical acceptable salt thereof; [ka] In the formula, R is H or lower alkyl having 1 to 6 carbon atoms. method.

[0152] [Appendix 4] 4. The method of claim 1 or 3, further comprising administering a thyroid hormone in combination with the RXR agonist.

[0153] [Appendix 5] The method of claim 1 or 3, wherein the RXR agonist is a compound of formula II. [ka]

[0154] [Appendix 6] 4. The method of claim 1 or 3, wherein the Her2 targeted therapy comprises an anti-Her2 therapeutic antibody.

[0155] [Appendix 7] 7. The method of claim 6, wherein the therapeutic antibody is trastuzumab or pertuzumab.

[0156] [Appendix 8] 4. The method of claim 1 or 3, wherein the Her2 targeted therapy comprises an antibody-drug conjugate, and the antibody is an anti-Her2 antibody.

[0157] [Appendix 9] 4. The method of claim 1 or 3, wherein the Her2 targeted therapeutic comprises a Her2 kinase inhibitor.

[0158] [Appendix 10] The method of claim 9, wherein the Her2 kinase inhibitor is lapatinib, neratinib, or tucatinib.

[0159] [Appendix 11] The method of claim 9, wherein the Her2 kinase inhibitor comprises afatinib, dacomitinib, canertinib, sapitinib, CP-724714, or CUDC-101.

[0160] [Appendix 12] Her2 + Cancer is Her2 + 13. The method of any one of claims 1 to 12, wherein the cancer is breast cancer.

[0161] [Appendix 13] Her2 resistant to Her2 targeted drugs + The method of any one of claims 1 to 3, wherein the cancer is also resistant to the RXR agonist of formula I.

[0162] [Appendix 14] The method of claim 1, 3, or 13, wherein the combination of the Her2 targeted therapeutic agent and the RXR agonist inhibits tumor cell proliferation, and the inhibition of tumor cell proliferation by the combination is greater than the additive inhibitory effect of each of the Her2 targeted therapeutic agent and the RXR agonist alone.

Claims

1. Her2 resistant to at least one Her2-targeted therapeutic agent ＋ 1. A pharmaceutical composition for a method of treating a patient with cancer, comprising: The present invention comprises a retinoid X receptor (RXR) agonist of Formula I or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 wherein R is H or lower alkyl having 1 to 6 carbon atoms; the patient has been or is currently being administered the Her2 targeted therapy; Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein the method further comprises administering the Her2 targeted therapeutic agent.

3. Her2 patients receiving treatment with Her2 targeted drugs ＋ 1. A pharmaceutical composition for a method of treating a patient with cancer, comprising: the cancer has become resistant to the Her2 targeted therapeutic agent; The method includes continuing treatment with the Her2 targeted therapeutic agent and initiating treatment with an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof; 【Chemistry 2】 wherein R is H or lower alkyl having 1 to 6 carbon atoms; The pharmaceutical composition comprises the RXR agonist or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions.

4. The pharmaceutical composition of claim 1 or 3, wherein the method further comprises administering a thyroid hormone in combination with the RXR agonist.

5. 4. The pharmaceutical composition of claim 1 or 3, wherein the RXR agonist is a compound of formula II. 【Transformation 3】

6. 10. The pharmaceutical composition of claim 1 or 3, wherein the Her2 targeted therapeutic agent comprises an anti-Her2 therapeutic antibody.

7. 7. The pharmaceutical composition of claim 6, wherein the therapeutic antibody is trastuzumab or pertuzumab.

8. 10. The pharmaceutical composition of claim 1 or 3, wherein the Her2 targeted therapeutic agent comprises an antibody-drug conjugate, and the antibody is an anti-Her2 antibody.

9. 10. The pharmaceutical composition of claim 1 or 3, wherein the Her2 targeted therapeutic agent comprises a Her2 kinase inhibitor.

10. 10. The pharmaceutical composition of claim 9, wherein the Her2 kinase inhibitor is lapatinib, neratinib, or tucatinib.

11. 10. The pharmaceutical composition of claim 9, wherein the Her2 kinase inhibitor comprises afatinib, dacomitinib, canertinib, sapitinib, CP-724714, or CUDC-101.

12. Her2 ＋ Cancer is Her2 ＋ The pharmaceutical composition according to claim 1 or 3, wherein the treatment is breast cancer.

13. Her2 resistant to Her2 targeted therapeutic drug ＋ 10. The pharmaceutical composition of claim 1 or 3, wherein the cancer is also resistant to said RXR agonist of formula I.

14. 4. The pharmaceutical composition of claim 1 or 3, wherein the combination of the Her2 targeted therapeutic agent and the RXR agonist inhibits tumor cell proliferation, and the inhibition of tumor cell proliferation by the combination is greater than the additive inhibitory effect of each of the Her2 targeted therapeutic agent and the RXR agonist alone.

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