Therapeutic compositions and methods for treating cancer

Abstract

The present disclosure provides therapeutic combinations that provide a synergistic effect in the treatment of cancer. The present disclosure provides methods of treatment comprising administration of the combination, and uses of the combination, e.g., in the treatment of cancer.

Description

[0001] This application is a divisional application based on Chinese patent application No. 202080057628.9.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 864,870, filed on June 21, 2019, and U.S. Provisional Application No. 63 / 031,749, filed on May 29, 2020, the entire disclosures of which are hereby incorporated by reference herein. Background Art

[0004] Cancer is a general term used to describe diseases in which abnormal cells divide uncontrollably. Cancer cells can invade neighboring tissues and can spread to other parts of the body through the bloodstream and lymphatic system. There are different types of cancer, such as bladder cancer, breast cancer, colon cancer, rectal cancer, head and neck cancer, endometrial cancer, kidney (renal cell) cancer, leukemia, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, non-Hodgkin lymphoma, and melanoma. After skin cancer, breast cancer is the most common cancer in women.

[0005] There is a need to develop new treatments for cancer, including but not limited to breast cancer. Summary of the invention

[0006] The present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of defatinib. In some embodiments, idelalisib and defatinib are provided in a synergistically effective amount. In some embodiments, the molar ratio of idelalisib to defatinib is 2:1 to 4:1.

[0007] In some embodiments, the present disclosure also provides a method for treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a drug combination to the subject. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the cancer is luminal A breast cancer. In some embodiments, the cancer is luminal B breast cancer. In some embodiments, the cancer is Her2-enriched breast cancer. In some embodiments, the cancer is normal breast-like breast cancer. In some embodiments, the cancer is basal cell-like breast cancer. In some embodiments, the combination of idelalis and difatinib is at least twice as effective in killing malignant cells as it is in killing non-malignant cells. In some embodiments, idelalis and difatinib are administered simultaneously. In some embodiments, idelalis and difatinib are administered sequentially.

[0008] The present disclosure also provides a method for treating triple-negative breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount. In some embodiments, the molar ratio of ribociclib to dabrafenib is 2:1 to 1:2. In some embodiments, the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In some embodiments, ribociclib and dabrafenib are administered simultaneously. In some embodiments, ribociclib and dabrafenib are administered sequentially.

[0009] The present disclosure also provides a method for treating luminal A breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount. In some embodiments, the molar ratio of ribociclib to dabrafenib is 2:1 to 1:2. In some embodiments, the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In some embodiments, ribociclib and dabrafenib are administered simultaneously. In some embodiments, ribociclib and dabrafenib are administered sequentially.

[0010] The present disclosure also provides a method for treating luminal B breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount. In some embodiments, the molar ratio of ribociclib to dabrafenib is 2:1 to 1:2. In some embodiments, the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In some embodiments, ribociclib and dabrafenib are administered simultaneously. In some embodiments, ribociclib and dabrafenib are administered sequentially.

[0011] The present disclosure also provides a method for treating Her2-enriched breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount. In some embodiments, the molar ratio of ribociclib to dabrafenib is 2:1 to 1:2. In some embodiments, the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In some embodiments, ribociclib and dabrafenib are administered simultaneously. In some embodiments, ribociclib and dabrafenib are administered sequentially.

[0012] The present disclosure also provides a method for treating normal breast-like breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount. In some embodiments, the molar ratio of ribociclib to dabrafenib is 2:1 to 1:2. In some embodiments, the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In some embodiments, ribociclib and dabrafenib are administered simultaneously. In some embodiments, ribociclib and dabrafenib are administered sequentially.

[0013] The present disclosure also provides a method for treating basal cell-like breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount. In some embodiments, the molar ratio of ribociclib to dabrafenib is 2:1 to 1:2. In some embodiments, the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In some embodiments, ribociclib and dabrafenib are administered simultaneously. In some embodiments, ribociclib and dabrafenib are administered sequentially.

[0014] The present disclosure also provides another drug combination, which comprises a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib. In some embodiments, niraparib and ixazomib are provided in a synergistically effective amount. In some embodiments, the molar ratio of niraparib to ixazomib is 312: 1 to 1250: 1. In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the pharmaceutical composition to the subject. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the cancer is luminal A breast cancer. In some embodiments, the cancer is luminal B breast cancer. In some embodiments, the cancer is Her2-enriched breast cancer. In some embodiments, the cancer is normal breast-like breast cancer. In some embodiments, the cancer is basal cell-like breast cancer. In some embodiments, niraparib and ixazomib are administered simultaneously. In some embodiments, niraparib and ixazomib are administered sequentially.

[0015] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of bortezomib and a therapeutically effective amount of lapatinib. In some embodiments, the cancer is breast cancer.

[0016] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of bortezomib and a therapeutically effective amount of ensidipine. In some embodiments, the cancer is breast cancer.

[0017] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of bortezomib and a therapeutically effective amount of abemaciclib. In some embodiments, the cancer is breast cancer.

[0018] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib. In some embodiments, the cancer is breast cancer.

[0019] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of oprazomib and a therapeutically effective amount of robrutinib. In some embodiments, the cancer is breast cancer.

[0020] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of masitinib and a therapeutically effective amount of larotrectinib. In some embodiments, the cancer is breast cancer.

[0021] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of masitinib and a therapeutically effective amount of sonidegi. In some embodiments, the cancer is breast cancer.

[0022] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of entospletinib and a therapeutically effective amount of idelalisib. In some embodiments, the cancer is breast cancer.

[0023] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of entospletinib and a therapeutically effective amount of bafitinib. In some embodiments, the cancer is breast cancer.

[0024] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of entospletinib and a therapeutically effective amount of defatinib. In some embodiments, the cancer is breast cancer.

[0025] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of idelalisib and a therapeutically effective amount of defatinib. In some embodiments, the cancer is breast cancer.

[0026] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ensidipine and a therapeutically effective amount of lapatinib. In some embodiments, the cancer is breast cancer.

[0027] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of fotatinib and a therapeutically effective amount of acalabrutinib. In some embodiments, the cancer is breast cancer.

[0028] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of fostamatinib and a therapeutically effective amount of duvelisib. In some embodiments, the cancer is breast cancer.

[0029] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, the cancer is breast cancer.

[0030] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of derazantinib and a therapeutically effective amount of dabrafenib. In some embodiments, the cancer is breast cancer.

[0031] The present disclosure also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of bortezomib and a therapeutically effective amount of delazentinib. In some embodiments, the cancer is breast cancer.

[0032] The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of acalabrutinib to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of bafitinib to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of defatinib to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of ensidipine to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of entospletinib to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of oprazombe to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of robutinib to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of fotatinib to the subject. The present disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of delazentinib to the subject.

[0033] As non-limiting examples, the present application provides the following embodiments:

[0034] Embodiment 1. A pharmaceutical composition comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of defatinib.

[0035] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein idelalisib and defatinib are provided in synergistically effective amounts.

[0036] Embodiment 3. The pharmaceutical composition of embodiment 1, wherein the molar ratio of idelalisib to defatinib is 2:1 to 4:1.

[0037] Embodiment 4. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-3.

[0038] Embodiment 5. The method of embodiment 4, wherein the cancer is breast cancer.

[0039] Embodiment 6. The method of embodiment 5, wherein the cancer is triple-negative breast cancer.

[0040] Embodiment 7. The method of embodiment 5, wherein the cancer is luminal A breast cancer.

[0041] Embodiment 8. The method of embodiment 5, wherein the cancer is luminal B breast cancer.

[0042] Embodiment 9. The method of embodiment 5, wherein the cancer is Her2-enriched breast cancer.

[0043] Embodiment 10. The method of embodiment 5, wherein the cancer is normal breast-like breast cancer.

[0044] Embodiment 11. The method of embodiment 5, wherein the cancer is basal-like breast cancer.

[0045] 12. The method of any one of embodiments 4-11, wherein the combination of idelalisib and defatinib is at least two times more effective in killing malignant cells than it is in killing non-malignant cells.

[0046] Embodiment 13. The method of any one of embodiments 4-12, wherein idelalisib and defatinib are administered simultaneously.

[0047] Embodiment 14. The method of any one of embodiments 4-12, wherein idelalisib and defatinib are administered sequentially.

[0048] Embodiment 15. A method of treating triple-negative breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

[0049] Embodiment 16. A method of treating luminal A breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

[0050] Embodiment 17. A method of treating luminal B breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

[0051] Embodiment 18. A method of treating Her2-enriched breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

[0052] Embodiment 19. A method of treating normal breast-like breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

[0053] Embodiment 20. A method of treating basal-like breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

[0054] Embodiment 21. The method of any one of embodiments 15-20, wherein ribociclib and dabrafenib are provided in synergistically effective amounts.

[0055] 22. The method of any one of embodiments 15-20, wherein the molar ratio of ribociclib to dabrafenib is 2:1 to 1:2.

[0056] Embodiment 23. The method of any one of embodiments 15-22, wherein the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells.

[0057] Embodiment 24. The method of any one of embodiments 15-23, wherein ribociclib and dabrafenib are administered simultaneously.

[0058] Embodiment 25. The method of any one of embodiments 15-23, wherein ribociclib and dabrafenib are administered sequentially.

[0059] Embodiment 26. A pharmaceutical composition comprising a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib.

[0060] Embodiment 27. The pharmaceutical composition of embodiment 26, wherein niraparib and ixazomib are provided in synergistically effective amounts.

[0061] Embodiment 28. The pharmaceutical composition of embodiment 26, wherein the molar ratio of niraparib to ixazomib is 312:1 to 1250:1.

[0062] Embodiment 29. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination of any one of Embodiments 26-28.

[0063] Embodiment 30. The method of embodiment 29, wherein the cancer is breast cancer.

[0064] Embodiment 31. The method of embodiment 30, wherein the cancer is triple-negative breast cancer.

[0065] Embodiment 32. The method of embodiment 30, wherein the cancer is luminal A breast cancer.

[0066] Embodiment 33. The method of embodiment 30, wherein the cancer is luminal B breast cancer.

[0067] Embodiment 34. The method of embodiment 30, wherein the cancer is Her2-enriched breast cancer.

[0068] Embodiment 35. The method of embodiment 30, wherein the cancer is normal breast-like breast cancer.

[0069] Embodiment 36. The method of embodiment 30, wherein the cancer is basal-like breast cancer.

[0070] Embodiment 37. The method of any one of embodiments 29-36, wherein niraparib and ixazomib are administered simultaneously.

[0071] Embodiment 38. The method of any one of embodiments 29-36, wherein niraparib and ixazomib are administered sequentially. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 is a schematic representation of the signaling pathway that is targeted.

[0073] Figure 2 is a diagram showing the target confirmation workflow.

[0074] Figure 3 is a graph showing the dose range and IC50 values ​​of the following drugs: abemaciclib ( Figure 3 A), Bafitinib ( Figure 3 B), bortezomib ( Figure 3 C), dabrafenib ( Figure 3 D), Difatinib ( Figure 3 E), derazantinib ( Figure 3 F), Duvelisib ( Figure 3 G), Ensidipine ( Figure 3 H), erismodegib / sonidegib ( Figure 3 I), fostamatinib ( Figure 3 J), ixazomib ( Figure 3 K), lapatinib ( Figure 3 L), Masitinib ( Figure 3 M), Opzomib ( Figure 3 N); and in T4-2 cells ( Figure 3 O) of Riboxini.

[0075] Figure 4 is a table showing IC50 values ​​determined by drug response assays.

[0076] Figure 5 Figure 2 shows the effect of niraparib and ixazomib on 2D culture in a 6×6 matrix ( Figure 5 The dose results on A) Figure 5 B) Table of; Readout: cell survival.

[0077] Figure 6 is a graph showing the viable fraction of S1 and T4-2 cells treated with various concentrations (v / v) of DMSO.

[0078] Figure 7 is a schematic diagram showing the process of translational assay in 3D LrECM culture.

[0079] Figure 8 is a set of graphs showing live cells, dead cells, and DNA of S1 and T4-2 cells treated with different drugs and drug combinations. Figure 8 A includes images of bortezomib, lapatinib, bortezomib + lapatinib, ensidipine, bortezomib + ensidipine, acibelib, and bortezomib + acibelib; Figure 8 B includes images of niraparib, ixazomib, niraparib + ixazomib, oprazomib, robustinib, and oprazomib + robustinib; Figure 8 The C includes images of masitinib, larotrectinib, masitinib + larotrectinib, sonidegi, and masitinib + sonidegi; Figure 8 The D includes images for entospletinib, idelalisib, entospletinib + idelalisib, barifitinib, and entospletinib + barifitinib; Figure 8 E includes images of defatinib, defatinib + entospletinib, idelalisib + defatinib, and ensidipine + lapatinib; Figure 8 The F includes images of fostamatinib, acalabrutinib, fostamatinib + acalabrutinib, duvelixib, and fostamatinib + duvelixib; Figure 8 The G includes images for dabrafenib, ribociclib, ribociclib + dabrafenib, derafenib, derafenib + dabrafenib, and bortezomib + derafenib.

[0080] Fig. 9 are histograms showing the percentage of cell death of S1 and T4-2 cells treated with various drugs and drug combinations.

[0081] Fig.10 is a schematic outlining the effects of drugs on non-malignant and malignant breast epithelial cells in 3D culture.

[0082] Fig.11 is a table showing the results of compound combinations tested for synergistic doses on a 6×6 matrix on 2D culture; the combinations include barfitinib and entospletinib ( Fig.11 A), lapatinib and ensidipine ( Fig.11 B), derazantinib and bortezomib ( Fig.11 C), bortezomib and ensidipine ( Fig.11 D), Robutinib and Oprazomib ( Fig.11 E), bortezomib and aciberib ( Fig.11 F), larotrectinib sulfate and masitinib ( Fig.11 G), idelalisib and entospletinib ( Fig.11 H), lapatinib and bortezomib ( Fig.11 I), erismodegib, and masitinib ( Fig.11 J), acalabrutinib and fostamatinib ( Fig.11 K), dabrafenib and ribociclib ( Fig.11 L), duveliximab and fostamatinib ( Fig.11 M), dabrafenib and derazantinib ( Fig.11 N), ixazomib and niraparib ( Fig.11 O), defatinib and entospletinib ( Fig.11 of P), lapatinib and ensidipine ( Fig.11 Q), defatinib and idelalisib ( Fig.11 of R). DETAILED DESCRIPTION

[0083] The present disclosure provides combinations of chemotherapeutic agents that have been unexpectedly found to be synergistically effective in treating various cancers. Combinations include idelalisib and defatinib, ribociclib and dabrafenib, and niraparib and ixazomib. In some embodiments, the cancer to be treated is triple-negative breast cancer. In some embodiments, the cancer to be treated is luminal A breast cancer. In some embodiments, the cancer to be treated is luminal B breast cancer. In some embodiments, the cancer to be treated is Her2-enriched breast cancer. In some embodiments, the cancer to be treated is normal breast-like breast cancer. In some embodiments, the cancer to be treated is basal cell-like breast cancer.

[0084] definition

[0085] It should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting. As used in this specification and the appended claims, the singular forms "a / an" and "the" include plural indicators unless the context clearly dictates otherwise. Thus, for example, reference to an "excipient" includes a combination of two or more such excipients, reference to an "active pharmaceutical ingredient" includes one or more active pharmaceutical ingredients, etc. Unless otherwise specified or apparent from the context, as used herein, the term "or" is understood to be inclusive and covers both "or" and "and".

[0086] As used in this application, the terms "about" and "approximately" are used as equivalents. Any number used in this application with or without about / approximately is intended to cover any normal fluctuations understood by a person of ordinary skill in the relevant art. In certain embodiments, unless otherwise specified or apparent from the context, the term "about" or "approximately" refers to a 5% or smaller value range (unless the number exceeds 100% of the possible value) falling within the reference value in either direction (greater than or less than).

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although other methods, systems and networks similar or equivalent to those described herein can be used to implement the present invention, preferred materials and methods are described herein.

[0088] In describing and claiming the present invention, the following terminology will be used in accordance with the definitions listed below.

[0089] As used herein, the terms "subject" and "patient" refer to any member of the subphylum Chordata, including, but not limited to, humans and other primates, including non-human primates such as rhesus monkeys and other monkey species and chimpanzees and other ape species; farm animals such as cattle, sheep, pigs, goats, and horses; domestic mammals such as dogs and cats; laboratory animals, including rodents such as mice, rats, and guinea pigs; birds, including poultry, wild birds, and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, etc. The term does not denote a particular age or sex. Thus, it is intended to cover both adult and newborn individuals.

[0090] As used herein, the terms "administer" and "administering" refer to providing a therapeutic agent to a subject. There are a variety of techniques for administering therapeutic agents in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration. In some embodiments, administration is oral administration.

[0091] As used herein, the terms "treatment" and "treating" refer to the improvement of a disease or condition, or at least one sign or symptom thereof. "Treatment" or "treating" may refer to reducing the progression of a disease or condition, such as by, for example, stabilization of at least one sign or symptom, or a reduction in the rate of progression as determined by a reduction in the rate of progression of at least one sign or symptom. In another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or condition.

[0092] As used herein, the term "therapeutically effective amount" refers to the amount of a drug, formulation, or composition that achieves a specific biological result. In certain embodiments, a therapeutically effective amount treats or prevents a disease or condition, e.g., ameliorates at least one sign or symptom of the condition. In various embodiments, the disease or condition is cancer.

[0093] As used herein, the compounds disclosed herein include pharmaceutically acceptable forms thereof. Some examples of compounds include, but are not limited to, idelalisib, defatinib, ribociclib, niraparib, and ixazomib. As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, esters, and isotopically labeled derivatives of the disclosed compounds. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, isomers, and prodrugs.

[0094] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. Compounds that are basic in nature and included in the compositions of the present invention are capable of forming a variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, which are salts containing pharmaceutically acceptable anions, including, but not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, fumarate, gluconate, glucaronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. In addition to the above-mentioned acids, the compounds including the amino moiety included in the compositions of the present invention can also form pharmaceutically acceptable salts with various amino acids. The compounds included in the compositions of the present invention that are acidic in nature can form basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

[0095] In some embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate can be a disclosed compound or a pharmaceutically acceptable salt thereof. In the case where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that can, for example, include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4 solvent molecules or water molecules. It should be understood that the term "compound" as used herein includes compounds and solvates of compounds, and mixtures thereof.

[0096] In some embodiments, pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to a compound that is transformed in vivo to produce a disclosed compound or a pharmaceutically acceptable form of the compound. Prodrugs may be inactive when administered to a subject, but are converted into active compounds in vivo, such as by hydrolysis (e.g., hydrolysis in blood). In some cases, prodrugs have improved physical and / or delivery properties compared to the parent compound. Prodrugs are generally designed to enhance the properties based on pharmacy and / or pharmacokinetic properties associated with the parent compound. Exemplary advantages of prodrugs may include, but are not limited to, their physical properties, such as, compared to the parent compound, water solubility for parenteral administration enhanced at physiological pH, or it enhances the absorption of the digestive tract, or it can enhance drug stability for long-term storage.

[0097] The term "prodrug" is also intended to include any covalently bound carriers that release the active compound in vivo when such prodrugs are administered to a subject. As described herein, prodrugs of active compounds can be prepared by modifying functional groups present in the active compound in such a way that the modification is cleaved into the parent active compound in routine manipulation or in vivo. Prodrugs include compounds in which hydroxyl, amino or sulfhydryl groups are bound to any group that, when the prodrug of the active compound is administered to a subject, is cleaved to form free hydroxyl, free amino or free sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols or acetamides, formamide and benzamide derivatives of amine functional groups in active compounds, and the like.

[0098] In some embodiments, the pharmaceutically acceptable form is an isomer. "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include geometric double bond cis and trans isomers, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures of the above; and other mixtures of the above, all fall within the scope of the present disclosure.

[0099] The term "synergy" or "synergistic" includes a more than additive effect of the combination of two or more agents compared to their individual effects. In certain embodiments, synergy or a synergistic effect refers to the beneficial effects of using two or more agents in combination, for example, in a pharmaceutical composition or method of treatment.

[0100] In some embodiments, a synergistic effect is an effect that requires a lower dose of one or both agents to achieve an effect. For example, when at least one agent is administered at a dose lower than the dose of the agent required to achieve the same therapeutic effect (when the agent is administered as a monotherapy), the combination can provide a selected effect, such as a therapeutic effect. In certain embodiments, the combination of a first agent and a second agent allows the first agent to be administered at a dose lower than the dose required to achieve the same therapeutic effect if the first agent is administered as a monotherapy.

[0101] In some embodiments, a synergistic effect is a reduction, prevention, delay or decrease in the occurrence or likelihood of development of one or more side effects, toxicity, resistance, or other effects that would otherwise be associated with the administration of at least one of the agents.

[0102] In some embodiments, the synergistic effect is a reduction in resistance (eg, a reduction in a measure of resistance or a reduction in the likelihood of developing resistance), or a delay in the development of resistance to at least one agent.

[0103] Combination therapy or "in combination with" refers to the use of more than one compound or agent to treat a particular disorder or condition. For example, Compound 1 can be administered in combination with at least one additional therapeutic agent. By "in combination," it is not intended to mean that the other therapy and Compound 1 must be administered simultaneously and / or formulated for delivery together, although these delivery methods are within the scope of the present disclosure. Compound 1 can be administered simultaneously with one or more other additional agents, or before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after) one or more other additional agents. In general, each therapeutic agent will be administered at a dose and / or schedule determined for that particular agent. Other therapeutic agents can be administered separately with Compound 1 herein in a single composition or in different compositions.

[0104] The term "synergistic effect" refers to the interaction or cooperation of two or more substances to produce a combined effect greater than the sum of their individual effects. There are several models to measure synergy, including the highest single agent model (HSA), the Loewe additivity model, and the Bliss independence model, which are discussed in Berenbaum MC. Pharmacol Rev. 1989; 41: 93–141; Loewe S. Arzne imittel-forschung. 1953; 3: 285–290 and Bliss CI. Ann Appl Biol. 1939; 26: 585–615, which are incorporated herein by reference in their entirety. Any method for measuring synergy can be used.

[0105] The term "cancer" includes, but is not limited to, solid tumors and blood-borne tumors. The term "cancer" refers to diseases of the skin tissues, organs, blood and blood vessels, including, but not limited to, bladder cancer, bone cancer or blood cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, laryngeal cancer and uterine cancer.

[0106] The term "triple negative breast cancer" or "TNBC" refers to any breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR) and Her2 / neu genes. The term includes primary epithelial TNBC, as well as TNBC involving other tumors. Cancer can include triple negative breast cancer, ductal carcinoma, lobular carcinoma, undifferentiated breast cancer, cystosarcoma phyllodes of the breast, angiosarcoma of the breast, and primary lymphoma of the breast. TNBC can also include triple negative breast cancer of any stage, and can include breast tumors with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0107] Idelalis is an orally bioavailable small molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class I phosphoinositide 3-kinase (PI3K) with potential immunomodulatory and anti-tumor activities. Idelalis' chemical name is 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4-one and has the structure of formula (I):

[0108]

[0109] Defatinib is an orally bioavailable small molecule focal adhesion kinase (FAK) inhibitor with potential anti-angiogenic and anti-tumor activities. The chemical name of defatinib is N-methyl-4-[[4-[[3-[methyl(methylsulfonyl)amino]pyrazin-2-yl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide, and has the structure of formula (II):

[0110]

[0111] Ribociclib is an orally available cyclin-dependent kinase (CDK) inhibitor targeting the cyclin D1 / CDK4 and cyclin D3 / CDK6 cell cycle pathways with potential anti-tumor activity. Ribociclib is also known as LEE011, LEE-011 and Kisqali. The chemical name of ribociclib is 7-cyclopentyl-N,N-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide, and has the structure of formula (III):

[0112]

[0113] Niraparib is an orally bioavailable inhibitor of poly (ADP-ribose) polymerase (PARP) types 1 and 2 (PARP-1 and PARP-2) with anti-tumor activity. Niraparib is also known as MK-4827, (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide and ZEJULA. The chemical name of niraparib is 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide and has the structure of formula (IV):

[0114]

[0115] Ixazomib is the active metabolite of MLN9708 and is a second-generation boron-containing peptide proteasome inhibitor (PI) with potential anti-tumor activity. The proteasome is a large protease complex that degrades unwanted or damaged proteins that have been ubiquitinated. Ixazomib is also known as MLN-2238. The chemical name of Ixazomib is [(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid and has the structure of formula (V):

[0116]

[0117] Ensidipine is an orally available inhibitor of a specific mutant form of the mitochondrial enzyme isocitrate dehydrogenase type 2 (IDH2) with potential anti-tumor activity. Ensidipine is also known as AG-221, IDHIFA, and UNII-3T1SS4E7AG. Ensidipine's chemical name is 2-methyl-1-[[4-[6-(trifluoromethyl)pyridin-2-yl]-6-[[2-(trifluoromethyl)pyridin-4-yl]amino]-1,3,5-triazin-2-yl]amino]propan-2-ol, or has the structure of formula (VI):

[0118]

[0119] Aciberib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways and has potential anti-tumor activity. Aciberib is also known as LY2835219 and Verzenio. Aciberib has the chemical name N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine and has a chemical structure of formula (VII):

[0120]

[0121] Oprozomib is an orally bioavailable proteasome inhibitor with potential anti-tumor activity. Oprozomib is also known as ONX-0912. The chemical name of oprozomib is N-[(2S)-3-methoxy-1-[[(2S)-3-methoxy-1-[[(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide (N-[(2S)-3-methoxy-1-[[(2S)-3-methoxoxan-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide). y-1-[[(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide), and has a chemical structure of formula (VIII):

[0122]

[0123] Robustinib, also known as FGF-401, is a highly selective and potent FGFR4 inhibitor. Robustinib's chemical name is N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-formyl-6-[(4-methyl-2-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide, and has a chemical structure of formula (IX):

[0124]

[0125] Larotrectinib is an orally available tropomyosin receptor kinase (Trk) inhibitor with potential anti-tumor activity. Larotrectinib is also known as ARRY-470, UNII-PF9462I9HX, and LOXO-101. Larotrectinib's chemical name is (3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridin-3-yl]-3-hydroxypyrrolidine-1-carboxamide, and has a chemical structure of formula (X):

[0126]

[0127] Bafitinib is an orally active 2-phenylaminopyrimidine derivative with potential anti-tumor activity. Bafitinib is also known as INNO-406, NS-187, and UNII-NVW4Z03I9B. Bafitinib has the chemical name 4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyridin-5-ylpyridin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide and has the chemical structure of formula (XI):

[0128]

[0129] Acalabrutinib is an orally available inhibitor of Bruton's tyrosine kinase (BTK) with potential anti-tumor activity. Acalabrutinib is also known as ACP-196, Calquence, and UNII-I42748ELQW. The chemical name of acalabrutinib is 4-[8-amino-3-[(2S)-1-but-2-ynolpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide, and has a chemical structure of formula (XII):

[0130]

[0131] Sonidegib is an orally bioavailable small molecule smoothened (Smo) antagonist with potential anti-tumor activity. Sonidegib is also known as LDE225, NVP-LDE225 and Erismodegib. Sonidegib's chemical name is N-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide and has a chemical structure of formula (XIII):

[0132]

[0133] Duvelixib is an orally bioavailable, highly selective and potent small molecule inhibitor of phosphoinositide-3-kinase (PI3K) delta and gamma isoforms with potential immunomodulatory and anti-tumor activities. Duvelixib is also known as IPI-145 and INK-1197. Duvelixib has the chemical name (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and has the chemical structure of formula (XIV):

[0134]

[0135] Delazentinib is an orally bioavailable inhibitor of fibroblast growth factor receptor (FGFR) with potential anti-tumor activity. Delazentinib is also known as ARQ087 and UNII-N9B0H171MJ. Delazentinib's chemical name is (6R)-6-(2-fluorophenyl)-N-[3-[2-(2-methoxyethylamino)ethyl]phenyl]-5,6-dihydrobenzo[h]quinazolin-2-amine, and has a chemical structure of formula (XV):

[0136]

[0137] Bortezomib is a dipeptide boronic acid analog with antitumor activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquitinated proteins. Bortezomib is also known as Velcade, PS-341, and LDP-341. Bortezomib has the chemical name [(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propionyl]amino]butyl]boronic acid and has the chemical structure of formula (XVI):

[0138]

[0139] Dabrafenib is an orally bioavailable inhibitor of B-raf (BRAF) protein with potential anti-tumor activity. Dabrafenib is also known as Tafinlar or GSK2118436A. The chemical name of dabrafenib is N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, and has the chemical structure of formula (XVII):

[0140]

[0141] Entospletinib is an orally available inhibitor of spleen tyrosine kinase (Syk) with potential anti-tumor activity. Entospletinib is also known as GS-9973 and UNII-6I3O3W6O3B. Entospletinib's chemical name is 6-(1H-indazol-6-yl)-N-(4-morpholin-4-ylphenyl)imidazo[1,2-a]pyrazin-8-amine and has a chemical structure of formula (XVIII):

[0142]

[0143] Masitinib is a highly selective oral tyrosine kinase inhibitor. It is also known as AB1010. Masitinib's chemical name is 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-yl-1,3-thiazol-2-yl)amino]phenyl]benzamide, and has a chemical structure of formula (XIX):

[0144]

[0145] Fostamatinib, also known as R788, is a small molecule Syk kinase inhibitor with potential anti-inflammatory and immunomodulatory activities. The chemical name of Fostamatinib is [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate, and has a chemical structure of formula (XX):

[0146]

[0147] Lapatinib reversibly blocks the phosphorylation of epidermal growth factor receptor (EGFR), ErbB2, and Erk-1 and Erk-2, and AKT kinases; it also inhibits cyclin D protein levels in human tumor cell lines and xenografts. EGFR and ErbB2 are associated with the growth of various tumor types. Lapatinib is also known as Tykerb and GW572016. The chemical name of lapatinib is N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine, and has a chemical structure of formula (XXI):

[0148]

[0149] General Overview of the Invention

[0150] The present disclosure provides therapeutic combinations and methods for treating cancer.

[0151] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of defatinib. In one embodiment, idelalisib and defatinib are provided in synergistically effective amounts.

[0152] In some embodiments, the molar ratio of idelalisib or a pharmaceutically acceptable form thereof to defatinib or a pharmaceutically acceptable form thereof is 1:1 to 5:1. In some embodiments, the molar ratio of idelalisib or a pharmaceutically acceptable form thereof to defatinib or a pharmaceutically acceptable form thereof is 2:1 to 4:1. In some embodiments, the molar ratio of idelalisib or a pharmaceutically acceptable form thereof to defatinib or a pharmaceutically acceptable form thereof is about 2:1 or about 4:1. In some embodiments, the molar ratio of idelalisib or a pharmaceutically acceptable form thereof to defatinib or a pharmaceutically acceptable form thereof is 2:1 or 4:1.

[0153] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a drug combination comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of defatinib. In one embodiment, the cancer is breast cancer. In another embodiment, the cancer is triple-negative breast cancer.

[0154] In some embodiments, the present disclosure provides a method for treating an intrinsic subtype of breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a drug combination comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of difatinib. Classification of intrinsic subtypes of breast cancer can be performed, for example, using the PAM50 subtypes of genes, which classify breast cancer into one of five major subtypes based on their genetic characteristics: (1) luminal A type, (2) luminal B type, (3) normal breast-like type, (4) Her2-enriched type, and (5) basal cell-like type. In one embodiment, the cancer is luminal A type breast cancer. In another embodiment, the cancer is luminal B type breast cancer. In another embodiment, the cancer is normal breast-like type breast cancer. In another embodiment, the cancer is Her2-enriched type breast cancer. In another embodiment, the cancer is basal cell-like type breast cancer.

[0155] In some embodiments, the present disclosure provides a method for treating breast cancer characterized by the presence or absence of certain receptors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a drug combination, the drug combination comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of defatinib. In some embodiments, breast cancer is estrogen receptor positive. In some embodiments, breast cancer is estrogen receptor negative. In some embodiments, breast cancer is progesterone receptor positive. In some embodiments, breast cancer is progesterone receptor negative. In some embodiments, breast cancer is Her2 positive. In some embodiments, breast cancer is characterized by overexpression or amplified expression of Her2. In some embodiments, breast cancer is Her2 negative. In some embodiments, breast cancer is characterized by high levels of Ki-67. In some embodiments, breast cancer is characterized by low levels of Ki-67.

[0156] In some embodiments, breast cancer is estrogen receptor positive, progesterone receptor positive, Her2 negative, and characterized by low levels of Ki-67. In some embodiments, breast cancer is estrogen receptor positive, Her2 negative and characterized by high levels of Ki-67. In some embodiments, breast cancer is estrogen receptor positive, progesterone receptor positive, and characterized by overexpression or amplified expression of Her2. In some embodiments, breast cancer is estrogen receptor negative, progesterone receptor negative, and characterized by overexpression or amplified expression of Her2. In some embodiments, breast cancer is estrogen receptor negative, progesterone receptor negative and Her2 negative.

[0157] In another embodiment, the combination of idelalisib and defatinib is at least two times more effective at killing malignant cells than it is at killing non-malignant cells. In another embodiment, idelalisib and defatinib are administered simultaneously. In another embodiment, idelalisib and defatinib are administered sequentially.

[0158] In some embodiments, idelalisib and / or defatinib are administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0159] In some embodiments, the present disclosure provides a method of treating triple-negative breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In one embodiment, ribociclib and dabrafenib are provided in synergistically effective amounts.

[0160] In some embodiments, the present disclosure provides a method for treating an intrinsic subtype of breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. Classification of intrinsic subtypes of breast cancer can be performed, for example, using the PAM50 subtypes of genes, which classify breast cancer into one of five major subtypes based on their genetic characteristics: (1) luminal A type, (2) luminal B type, (3) normal breast-like type, (4) Her2-enriched type, and (5) basal cell-like type. In one embodiment, the cancer is luminal A type breast cancer. In another embodiment, the cancer is luminal B type breast cancer. In another embodiment, the cancer is normal breast-like type breast cancer. In another embodiment, the cancer is Her2-enriched type breast cancer. In another embodiment, the cancer is basal cell-like type breast cancer. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount.

[0161] In some embodiments, the present disclosure provides a method for treating breast cancer characterized by the presence or absence of certain receptors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib. In some embodiments, breast cancer is estrogen receptor positive. In some embodiments, breast cancer is estrogen receptor negative. In some embodiments, breast cancer is progesterone receptor positive. In some embodiments, breast cancer is progesterone receptor negative. In some embodiments, breast cancer is Her2 positive. In some embodiments, breast cancer is characterized by overexpression or amplified expression of Her2. In some embodiments, breast cancer is Her2 negative. In some embodiments, breast cancer is characterized by high levels of Ki-67. In some embodiments, breast cancer is characterized by low levels of Ki-67. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount.

[0162] In some embodiments, breast cancer is estrogen receptor positive, progesterone receptor positive, Her2 negative, and is characterized by low levels of Ki-67. In some embodiments, breast cancer is estrogen receptor positive, Her2 negative, and is characterized by high levels of Ki-67. In some embodiments, breast cancer is estrogen receptor positive, progesterone receptor positive, and is characterized by overexpression or amplified expression of Her2. In some embodiments, breast cancer is estrogen receptor negative, progesterone receptor negative, and is characterized by overexpression or amplified expression of Her2. In some embodiments, breast cancer is estrogen receptor negative, progesterone receptor negative and Her2 negative. In some embodiments, ribociclib and dabrafenib are provided in a synergistically effective amount.

[0163] In some embodiments, the molar ratio of ribociclib or a pharmaceutically acceptable form thereof to dabrafenib or a pharmaceutically acceptable form thereof is 1:2 to 6:1. In some embodiments, the molar ratio of ribociclib or a pharmaceutically acceptable form thereof to dabrafenib or a pharmaceutically acceptable form thereof is 1:1 to 4:1. In some embodiments, the molar ratio of ribociclib or a pharmaceutically acceptable form thereof to dabrafenib or a pharmaceutically acceptable form thereof is 2:1 to 4:1. In some embodiments, the molar ratio of ribociclib or a pharmaceutically acceptable form thereof to dabrafenib or a pharmaceutically acceptable form thereof is 1:1 to 2:1. In some embodiments, the molar ratio of ribociclib or a pharmaceutically acceptable form thereof to dabrafenib or a pharmaceutically acceptable form thereof is about 1:1, 2:1, 3:1 or 4:1. In some embodiments, the molar ratio of ribociclib or a pharmaceutically acceptable form thereof to dabrafenib or a pharmaceutically acceptable form thereof is 1:1, 2:1, 3:1 or 4:1.

[0164] In another embodiment, the combination of ribociclib and dabrafenib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, the combination of ribociclib and dabrafenib is at least 4 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, the combination of ribociclib and dabrafenib is at least 3 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, the combination of ribociclib and dabrafenib is at least 2 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, ribociclib and dabrafenib are administered simultaneously. In another embodiment, ribociclib and dabrafenib are administered sequentially.

[0165] In one embodiment, ribociclib and / or dabrafenib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0166] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib. In one embodiment, niraparib and ixazomib are provided in synergistically effective amounts.

[0167] In some embodiments, the molar ratio of niraparib or a pharmaceutically acceptable form thereof to ixazomib or a pharmaceutically acceptable form thereof is 1500: 1 to 1000: 1. In some embodiments, the molar ratio of niraparib or a pharmaceutically acceptable form thereof to ixazomib or a pharmaceutically acceptable form thereof is about 1500: 1, 1250: 1, or 1000: 1. In some embodiments, the molar ratio of niraparib or a pharmaceutically acceptable form thereof to ixazomib or a pharmaceutically acceptable form thereof is 1500: 1, 1250: 1, or 1000: 1.

[0168] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a drug combination comprising a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib. In one embodiment, the cancer is breast cancer. In another embodiment, the cancer is triple-negative breast cancer.

[0169] In some embodiments, the present disclosure provides a method for treating an intrinsic subtype of breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a drug combination comprising a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib. Classification of intrinsic subtypes of breast cancer can be performed, for example, using the PAM50 subtypes of genes, which classify breast cancer into one of five major subtypes based on their genetic characteristics: (1) luminal A type, (2) luminal B type, (3) normal breast-like type, (4) Her2-enriched type, and (5) basal cell-like type. In one embodiment, the cancer is luminal A type breast cancer. In another embodiment, the cancer is luminal B type breast cancer. In another embodiment, the cancer is normal breast-like type breast cancer. In another embodiment, the cancer is Her2-enriched type breast cancer. In another embodiment, the cancer is basal cell-like type breast cancer.

[0170] In some embodiments, the present disclosure provides a method for treating breast cancer characterized by the presence or absence of certain receptors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a drug combination, the drug combination comprising a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib. In some embodiments, the breast cancer is estrogen receptor positive. In some embodiments, the breast cancer is estrogen receptor negative. In some embodiments, the breast cancer is progesterone receptor positive. In some embodiments, the breast cancer is progesterone receptor negative. In some embodiments, the breast cancer is Her2 positive. In some embodiments, the breast cancer is characterized by overexpression or amplified expression of Her2. In some embodiments, the breast cancer is Her2 negative. In some embodiments, the breast cancer is characterized by high levels of Ki-67. In some embodiments, the breast cancer is characterized by low levels of Ki-67.

[0171] In some embodiments, the breast cancer is estrogen receptor positive, progesterone receptor positive, Her2 negative, and characterized by low levels of Ki-67. In some embodiments, the breast cancer is estrogen receptor positive, Her2 negative, and characterized by high levels of Ki-67. In some embodiments, the breast cancer is estrogen receptor positive, progesterone receptor positive, and characterized by overexpression or amplified expression of Her2. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor negative, and characterized by overexpression or amplified expression of Her2. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor negative, and Her2 negative.

[0172] In another embodiment, the combination of niraparib and ixazomib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, niraparib and ixazomib are administered simultaneously. In another embodiment, niraparib and ixazomib are administered sequentially.

[0173] In one embodiment, niraparib and / or ixazomib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0174] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of bafitinib and a therapeutically effective amount of entospletinib. In one embodiment, bafitinib and entospletinib are provided in synergistically effective amounts.

[0175] In some embodiments, the molar ratio of bafitinib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is 3: 1 to 1: 2. In some embodiments, the molar ratio of bafitinib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is about 2: 1 or 1: 1. In some embodiments, the molar ratio of bafitinib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is 2: 1 or 1: 1.

[0176] In another embodiment, the combination of bafitinib and entospletinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, bafitinib and entospletinib are administered simultaneously. In another embodiment, bafitinib and entospletinib are administered sequentially.

[0177] In one embodiment, barfitinib and / or entospletinib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0178] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of lapatinib and a therapeutically effective amount of ensidipine. In one embodiment, lapatinib and ensidipine are provided in synergistically effective amounts.

[0179] In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is 2: 1 to 1: 8. In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is about 1: 1, 1: 2, or 1: 4. In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is 1: 1, 1: 2, or 1: 4.

[0180] In another embodiment, the combination of lapatinib and ensidipine is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In another embodiment, lapatinib and ensidipine are administered simultaneously. In another embodiment, lapatinib and ensidipine are administered sequentially.

[0181] In one embodiment, lapatinib and / or ensidipine are administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0182] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of delazentinib and a therapeutically effective amount of bortezomib. In one embodiment, delazentinib and bortezomib are provided in synergistically effective amounts.

[0183] In some embodiments, the molar ratio of delazentinib or a pharmaceutically acceptable form thereof to bortezomib or a pharmaceutically acceptable form thereof is 1000: 1 to 4000: 1. In some embodiments, the molar ratio of delazentinib or a pharmaceutically acceptable form thereof to bortezomib or a pharmaceutically acceptable form thereof is about 1560: 1, 2000: 1, or 3125: 1. In some embodiments, the molar ratio of delazentinib or a pharmaceutically acceptable form thereof to bortezomib or a pharmaceutically acceptable form thereof is 1560: 1, 2000: 1, or 3125: 1.

[0184] In another embodiment, the combination of delazentinib and bortezomib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, delazentinib and bortezomib are administered simultaneously. In another embodiment, delazentinib and bortezomib are administered sequentially.

[0185] In one embodiment, derazentinib and / or bortezomib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0186] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of bortezomib and a therapeutically effective amount of ensidipine. In one embodiment, bortezomib and ensidipine are provided in synergistically effective amounts.

[0187] In some embodiments, the molar ratio of bortezomib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is 1:2000 to 1:30. In some embodiments, the molar ratio of bortezomib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is about 1:1000, 1:500, 1:250, 1:125, 2:125, or 4:125. In some embodiments, the molar ratio of bortezomib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is 1:1000, 1:500, 1:250, 1:125, 2:125, or 4:125.

[0188] In another embodiment, the combination of bortezomib and ensidipine is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, bortezomib and ensidipine are administered simultaneously. In another embodiment, bortezomib and ensidipine are administered sequentially.

[0189] In one embodiment, bortezomib and / or ensidipine are administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0190] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Robustinib and a therapeutically effective amount of Oprazomib. In one embodiment, Robustinib and Oprazomib are provided in synergistically effective amounts.

[0191] In some embodiments, the molar ratio of Robustinib or a pharmaceutically acceptable form thereof to Oprazomib or a pharmaceutically acceptable form thereof is 10,000: 1 to 1000: 1. In some embodiments, the molar ratio of Robustinib or a pharmaceutically acceptable form thereof to Oprazomib or a pharmaceutically acceptable form thereof is about 3125: 2. In some embodiments, the molar ratio of Robustinib or a pharmaceutically acceptable form thereof to Oprazomib or a pharmaceutically acceptable form thereof is 3125: 2.

[0192] In another embodiment, the combination of Robustinib and Oprazomib is at least 5 times more effective at killing malignant cells than it is at killing non-malignant cells. In another embodiment, Robustinib and Oprazomib are administered simultaneously. In another embodiment, Robustinib and Oprazomib are administered sequentially.

[0193] In one embodiment, Robustinib and / or oprazomib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0194] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of bortezomib and a therapeutically effective amount of aciberib. In one embodiment, bortezomib and aciberib are provided in synergistically effective amounts.

[0195] In some embodiments, the molar ratio of bortezomib or a pharmaceutically acceptable form thereof to aciberib or a pharmaceutically acceptable form thereof is 1:3000 to 1:500. In some embodiments, the molar ratio of bortezomib or a pharmaceutically acceptable form thereof to aciberib or a pharmaceutically acceptable form thereof is about 1:2000 or 1:1000. In some embodiments, the molar ratio of bortezomib or a pharmaceutically acceptable form thereof to aciberib or a pharmaceutically acceptable form thereof is 1:2000 or 1:1000.

[0196] In another embodiment, the combination of bortezomib and aciberib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, bortezomib and aciberib are administered simultaneously. In another embodiment, bortezomib and aciberib are administered sequentially.

[0197] In one embodiment, bortezomib and / or aciberib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0198] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of larotrectinib and a therapeutically effective amount of masitinib. In one embodiment, larotrectinib and masitinib are provided in synergistically effective amounts.

[0199] In some embodiments, the molar ratio of larotrectinib or a pharmaceutically acceptable form thereof to masitinib or a pharmaceutically acceptable form thereof is 20: 1 to 12: 1. In some embodiments, the molar ratio of larotrectinib or a pharmaceutically acceptable form thereof to masitinib or a pharmaceutically acceptable form thereof is about 16: 1. In some embodiments, the molar ratio of larotrectinib or a pharmaceutically acceptable form thereof to masitinib or a pharmaceutically acceptable form thereof is 16: 1.

[0200] In another embodiment, the combination of larotrectinib and masitinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, larotrectinib and masitinib are administered simultaneously. In another embodiment, larotrectinib and masitinib are administered sequentially.

[0201] In one embodiment, larotrectinib and / or masitinib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold less than the amount when administered alone.

[0202] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of entospletinib. In one embodiment, idelalisib and entospletinib are provided in synergistically effective amounts.

[0203] In some embodiments, the molar ratio of idelalisib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is 3:1 to 1:2. In some embodiments, the molar ratio of idelalisib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is about 2:1 or 1:1. In some embodiments, the molar ratio of idelalisib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is 2:1 or 1:1.

[0204] In another embodiment, the combination of idelalisib and entospletinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, idelalisib and entospletinib are administered simultaneously. In another embodiment, idelalisib and entospletinib are administered sequentially.

[0205] In one embodiment, idelalisib and / or entospletinib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0206] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of lapatinib and a therapeutically effective amount of bortezomib. In one embodiment, lapatinib and bortezomib are provided in synergistically effective amounts.

[0207] In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to bortezomib or a pharmaceutically acceptable form thereof is 300: 1 to 200: 1. In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to bortezomib or a pharmaceutically acceptable form thereof is about 250: 1. In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to bortezomib or a pharmaceutically acceptable form thereof is 249.6: 1.

[0208] In another embodiment, the combination of lapatinib and bortezomib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, lapatinib and bortezomib are administered simultaneously. In another embodiment, lapatinib and bortezomib are administered sequentially.

[0209] In one embodiment, lapatinib and / or bortezomib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0210] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of erismodegib and a therapeutically effective amount of masitinib. In one embodiment, erismodegib and masitinib are provided in synergistically effective amounts.

[0211] In some embodiments, the molar ratio of erismodegib or a pharmaceutically acceptable form thereof to masitinib or a pharmaceutically acceptable form thereof is 1: 1 to 10: 1. In some embodiments, the molar ratio of erismodegib or a pharmaceutically acceptable form thereof to masitinib or a pharmaceutically acceptable form thereof is about 2: 1, 4: 1, or 8: 1. In some embodiments, the molar ratio of erismodegib or a pharmaceutically acceptable form thereof to masitinib or a pharmaceutically acceptable form thereof is 2: 1, 4: 1, or 8: 1.

[0212] In another embodiment, the combination of erismodegib and masitinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, erismodegib and masitinib are administered simultaneously. In another embodiment, erismodegib and masitinib are administered sequentially.

[0213] In one embodiment, erismodegib and / or masitinib are administered in an amount that is reduced by the following folds compared to the amount when administered alone: ​​about 1.5 times to about 50 times, about 1.5 times to about 25 times, about 1.5 times to about 20 times, about 1.5 times to about 15 times, about 1.5 times to about 10 times, about 2 times to about 10 times, about 2 times to about 8 times, about 4 times to about 6 times, or about 5 times to about 6 times. In some embodiments, the present disclosure provides a drug conjugate comprising a therapeutically effective amount of acalabrutinib and a therapeutically effective amount of fotabrutinib. In one embodiment, acalabrutinib and fotabrutinib are provided in a synergistically effective amount.

[0214] In some embodiments, the molar ratio of acalabrutinib or a pharmaceutically acceptable form thereof to fostamatinib or a pharmaceutically acceptable form thereof is 1:2 to 6:1. In some embodiments, the molar ratio of acalabrutinib or a pharmaceutically acceptable form thereof to fostamatinib or a pharmaceutically acceptable form thereof is about 1:1, 2:1 or 4:1. In some embodiments, the molar ratio of acalabrutinib or a pharmaceutically acceptable form thereof to fostamatinib or a pharmaceutically acceptable form thereof is 1:1, 2:1 or 4:1.

[0215] In another embodiment, the combination of acalabrutinib and fostamatinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, acalabrutinib and fostamatinib are administered simultaneously. In another embodiment, acalabrutinib and fostamatinib are administered sequentially.

[0216] In one embodiment, acalabrutinib and / or fostamatinib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0217] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of duvelixib and a therapeutically effective amount of fostamatinib. In one embodiment, duvelixib and fostamatinib are provided in synergistically effective amounts.

[0218] In some embodiments, the molar ratio of duvelixib or a pharmaceutically acceptable form thereof to fostamatinib or a pharmaceutically acceptable form thereof is 1: 1 to 10: 1. In some embodiments, the molar ratio of duvelixib or a pharmaceutically acceptable form thereof to fostamatinib or a pharmaceutically acceptable form thereof is about 2: 1, 4: 1, or 8: 1. In some embodiments, the molar ratio of duvelixib or a pharmaceutically acceptable form thereof to fostamatinib or a pharmaceutically acceptable form thereof is 2: 1, 4: 1, or 8: 1.

[0219] In another embodiment, the combination of duvelixib and fostamatinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, duvelixib and fostamatinib are administered simultaneously. In another embodiment, duvelixib and fostamatinib are administered sequentially.

[0220] In one embodiment, duvelixib and / or fostamatinib are administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0221] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of dabrafenib and a therapeutically effective amount of delazentinib. In one embodiment, dabrafenib and delazentinib are provided in synergistically effective amounts.

[0222] In some embodiments, the molar ratio of dabrafenib or a pharmaceutically acceptable form thereof to delazentinib or a pharmaceutically acceptable form thereof is 3: 1 to 18: 1. In some embodiments, the molar ratio of dabrafenib or a pharmaceutically acceptable form thereof to delazentinib or a pharmaceutically acceptable form thereof is about 4: 1, 8: 1 or 16: 1. In some embodiments, the molar ratio of dabrafenib or a pharmaceutically acceptable form thereof to delazentinib or a pharmaceutically acceptable form thereof is 4: 1, 8: 1 or 16: 1.

[0223] In another embodiment, the combination of dabrafenib and delazentinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, dabrafenib and delazentinib are administered simultaneously. In another embodiment, dabrafenib and delazentinib are administered sequentially.

[0224] In one embodiment, dabrafenib and / or delazentinib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0225] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of defatinib and a therapeutically effective amount of entospletinib. In one embodiment, defatinib and entospletinib are provided in synergistically effective amounts.

[0226] In some embodiments, the molar ratio of defatinib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is 1:6 to 1:10. In some embodiments, the molar ratio of defatinib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is about 1:8. In some embodiments, the molar ratio of defatinib or a pharmaceutically acceptable form thereof to entospletinib or a pharmaceutically acceptable form thereof is 1:8.

[0227] In another embodiment, the combination of gefatinib and entospletinib is at least 5 times more effective in killing malignant cells than it is in killing non-malignant cells. In another embodiment, gefatinib and entospletinib are administered simultaneously. In another embodiment, gefatinib and entospletinib are administered sequentially.

[0228] In one embodiment, defatinib and / or entospletinib is administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0229] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of lapatinib and a therapeutically effective amount of ensidipine. In one embodiment, lapatinib and ensidipine are provided in synergistically effective amounts.

[0230] In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is 1:6 to 1:10. In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is about 1:8. In some embodiments, the molar ratio of lapatinib or a pharmaceutically acceptable form thereof to ensidipine or a pharmaceutically acceptable form thereof is 1:8.

[0231] In another embodiment, the combination of lapatinib and ensidipine is at least 5 times more effective in killing malignant cells than in killing non-malignant cells. In another embodiment, lapatinib and ensidipine are administered simultaneously. In another embodiment, lapatinib and ensidipine are administered sequentially.

[0232] In one embodiment, lapatinib and / or ensidipine are administered in an amount that is about 1.5-fold to about 50-fold, about 1.5-fold to about 25-fold, about 1.5-fold to about 20-fold, about 1.5-fold to about 15-fold, about 1.5-fold to about 10-fold, about 2-fold to about 10-fold, about 2-fold to about 8-fold, about 4-fold to about 6-fold, or about 5-fold to about 6-fold lower than the amount when administered alone.

[0233] Example

[0234] Example 1

[0235] 21 compounds were received and reconstituted to produce 10 mM stock solutions. These compounds are known to have Figure 1 Biological effects shown. Compounds were tested independently in 2D culture assays to determine cell viability. Combinations of compounds were then tested in 6×6 matrices on 2D cultures to determine synergistic doses. Functional validation of synergistic combinations was then determined in 3D cultures. (See Figure 2 ).

[0236] To determine the half maximal inhibitory concentration (IC 50 ), HMT 3522T4-2 human breast cancer cell line was seeded in 96-well plates at a density of 5 × 10 3 Non-malignant S1 cells were used as normal corresponding cell lines to compare cell survival rates, and cells were plated at 1×10 4 The cells were seeded at a density of 10 cells / well in H14 medium supplemented with epidermal growth factor (EGF). S1 and T4-2 cells were cultured for 18-20 hours before drug treatment, and eight concentration ranges (0, 0.0001, 0.001, 0.01, 0.1, 1, 10 and 100 μM) were prepared for each drug by serial dilution from the stock solution. The cells treated with drugs were cultured for 48 hours and then subjected to MTS colorimetric assay to obtain cell viability. The number of MTS colored products measured at 490 nm is proportional to the number of viable cells in the culture. Single drug dose response curves were fitted using nonlinear regression 4 parameters, and IC was determined using SigmaPlot software. 50 value( Figure 3-Figure 5 ). DMSO (solvent) added to the serial dilutions (up to 1%) showed minimal toxicity ( Figure 6 ).

[0237] To evaluate the dose response of the combination drug, a relative survival rate in a 6 × 6 dose matrix was designed, and the dose range was selected as the single drug IC 50 The range between values ​​( Figure 5Synergistic doses of compound combinations were tested in 2D cultures; the combination included bafitinib and entospletinib ( Fig.11 A), lapatinib and ensidipine ( Fig.11 B), derazantinib and bortezomib ( Fig.11 C), bortezomib and ensidipine ( Fig.11 D), Robutinib and Oprazomib ( Fig.11 E), bortezomib and aciberib ( Fig.11 F), larotrectinib sulfate and masitinib ( Fig.11 G), idelalisib and entospletinib ( Fig.11 H), lapatinib and bortezomib ( Fig.11 I), erismodegib, and masitinib ( Fig.11 J), acalabrutinib and fostamatinib ( Fig.11 K), dabrafenib and ribociclib ( Fig.11 L), duveliximab and fostamatinib ( Fig.11 M), dabrafenib and derazantinib ( Fig.11 N), ixazomib and niraparib ( Fig.11 O), defatinib and entospletinib ( Fig.11 of P), lapatinib and ensidipine ( Fig.11 Q), defatinib and idelalisib ( Fig.11 of R).

[0238] For 3D translation assays ( Figure 7 ), and the concentrations that showed synergistic inhibitory behavior in the dose response of the combination drugs obtained from the 6×6 dose matrix were selected. The determined concentrations were used to evaluate growth inhibition or cell death of non-malignant S1 and malignant T4-2 cells. Cells were plated at 2×10 4 (S1) or 1×10 4 (T4-2) cells were seeded on top of the Matrigel layer at a density of 100 cells / mL (T4-2) and allowed to form multicellular tumor colonies for 4-5 days. The cells were then treated with single drugs or drug combinations as PCIs designed to evaluate synergistic interactions. Fresh medium containing test drugs was replenished every other day. At the end of the assay, we analyzed morphology and viability / cytotoxicity using phase imaging and performed live / dead fluorescence detection using a viability / cytotoxicity (Calcein AM / EthD-1) kit ( Figure 8 ). The 3D translation assay of non-malignant S1 and malignant T4-2 cells was repeated three times. Figure 8 The results are summarized in Fig. 9 The bar graph shown.

[0239] The final data showed that ribociclib and dabrafenib, as well as idelalisib and defatinib, had significant synergistic interactions compared to either compound alone. Ribociclib plus dabrafenib treatment showed the most potent apoptotic phenotype in the combined treatment of malignant cells ( Figure 8 G), while non-malignant cells were unaffected. In addition, the combination of idelalisib and defatinib showed significant cytotoxicity in malignant cells. However, approximately 10%-15% of non-malignant cells were killed by this combination ( Figure 8 E), which may be due to the inhibition of FAK and PI3K, which are important for normal mammary gland development and survival. Dose adjustment may reduce cytotoxicity to normal cells. Oprozomib promotes cell proliferation in non-malignant S1 cells ( Figure 8 B). Combination treatment of oprozomib and robactinib leads to cell death in non-malignant S1 cells ( Figure 8 B). Oprazomib alone or in combination with robactinib may lead to adverse side effects in vivo. Niraparib and ixazomib also showed significant cytotoxicity in malignant cells. These results are summarized in Fig.10 middle.

[0240] While the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of idelalisib and a therapeutically effective amount of defatinib.

2. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1.

3. A method of treating triple-negative breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

4. A method of treating luminal A breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

5. A method of treating luminal B breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

6. A method of treating Her2-enriched breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

7. A method of treating normal breast-like breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

8. A method of treating basal-like breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ribociclib and a therapeutically effective amount of dabrafenib.

9. A pharmaceutical composition comprising a therapeutically effective amount of niraparib and a therapeutically effective amount of ixazomib.

10. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination of claim 9.

Images