WO2019169389A1 - Méthodes et compositions pour traiter le cancer et sensibiliser des cellules tumorales à des inhibiteurs de kinase - Google Patents

Méthodes et compositions pour traiter le cancer et sensibiliser des cellules tumorales à des inhibiteurs de kinase Download PDF

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WO2019169389A1
WO2019169389A1 PCT/US2019/020550 US2019020550W WO2019169389A1 WO 2019169389 A1 WO2019169389 A1 WO 2019169389A1 US 2019020550 W US2019020550 W US 2019020550W WO 2019169389 A1 WO2019169389 A1 WO 2019169389A1
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inhibitor
administered
erlotinib
kinase
kinase inhibitor
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PCT/US2019/020550
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English (en)
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Tony R. REID
Bryan ORONSKY
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Epicentrx, Inc.
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Publication of WO2019169389A1 publication Critical patent/WO2019169389A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • compositions and methods useful for treating cancer are provided.
  • Cancer is a significant health problem despite the many advances made for detecting and treating this disease.
  • Current strategies for managing cancer rely on early diagnosis and aggressive treatment. Treatment options often include surgery, radiotherapy, chemotherapy, hormone therapy, or a combination thereof. While such therapies provide a benefit to many patients, there is still a need for better therapeutic agents to treat various types of cancer.
  • Prostate cancer, breast cancer, and lung cancer are leading causes of cancer-related death.
  • Prostate cancer is the most common form of cancer among males, with an estimated incidence of 30% in men over the age of 50.
  • clinical evidence indicates that human prostate cancer has the propensity to metastasize to bone, and the disease appears to progress inevitably from androgen dependent to androgen refractory status, leading to increased patient mortality.
  • Breast cancer remains a leading cause of death in women. Its cumulative risk is relatively high; certain reports indicate that approximately one in eight women are expected to develop some type of breast cancer by age 85 in the United States.
  • lung cancer is a leading cause of cancer-related death, and non-small cell lung cancer (NSCLC) accounts for about 80% of these cases.
  • NSCLC non-small cell lung cancer
  • kinase inhibitors such as inhibitors of receptor tyrosine kinases
  • Many of these kinase inhibitors inhibit multiple kinases. Their therapeutic benefits thus are limited due to their toxicities.
  • a treatment for neoplasia and other proliferative disorders that enhances the anti-tumor activities of the kinase inhibitors without increasing the associated toxicities.
  • One aspect of the present disclosure provides methods for treating a subject having cancer, which comprises (a) administering to the subject an effective amount of a first kinase inhibitor; and (b) administering to the subject an effective amount of a second kinase inhibitor.
  • the first kinase inhibitor is administered before or concurrently with the second kinase inhibitor.
  • Another aspect of the present disclosure provides methods of treating a subject having cancer, which comprises (a) sensitizing cells of the cancer to a second kinase inhibitor by administering to the subject an effective amount of a first kinase inhibitor; (b) thereafter administering an effective amount of the second kinase to the subject.
  • Another aspect of the present disclosure provides methods of sensitizing cells of a cancer in a subject having the cancer to a second kinase inhibitor, which comprises administering to the subject an effective amount of first kinase inhibitor.
  • Another aspect of the present disclosure provides methods for sensitizing a solid tumor or hematologic tumor in a subject to a second kinase inhibitor, which comprises (a) administering to the subject an effective amount of a first kinase inhibitor; and (b) administering to the subject an effective amount of the second kinase inhibitor.
  • the administration of the first kinase inhibitor affects the pharmacokinetics and/or tolerability of a second kinase inhibitor in the subject.
  • the combination of the first kinase inhibitor and the second kinase inhibitor is sufficient to inhibit activity in cells required for growth of the solid or hematologic tumors, and wherein the cells are selected from the group consisting of cancer cells, cancer stem cells, stromal cells, and endothelial cells.
  • the solid tumor or hematologic tumor is resistant to the antitumor activity of the first kinase inhibitor and/or the second kinase inhibitor.
  • the first kinase inhibitor is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days before the second kinase inhibitor is administered to the subject. In certain embodiments, wherein the first kinase inhibitor is administered at least 1 to 96 hours before the second kinase inhibitor is administered to the subject.
  • compositions for the treatment of a subject having cancer or preventing the development of a tumor in a subject at risk of developing the tumor comprising (i) a first kinase inhibitor, and (ii) a second kinase inhibitor, and a pharmaceutically acceptable carrier.
  • the first kinase inhibitor is an EGFR inhibitor. In certain embodiments, the first kinase inhibitor is a specific EGFR inhibitor. In certain embodiments, the EGFR inhibitor is selected from the group consisting of erlotinib, gefitinib, icotinib, lapatinib, afatinib, neratinib, vandetanib, pelitinib, canertinib dacomitinib, BIBW 2992, and XL-647, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the EGFR inhibitor is selected from the group consisting of cetuximab, zalutumumab, or panitumumab, nimotuzumab, necitumumab, and matuzumab, and any combination thereof.
  • the second kinase inhibitor is a VEGFR-l inhibitor, VEGFR- 2 inhibitor, VEGFR-3 inhibitor, EGFR inhibitor, ErbB2 inhibitor, ErbB3 inhibitor, ErbB4 inhibitor, class 1 phosphatidylinositol 3 -kinase (PI3K) inhibitor, class 2 PI3K inhibitor, class 3 PI3K inhibitor, Bcr-Abl tyrosine-kinase inhibitor, PDGFR inhibitor, Raf inhibitor, and/or ⁇ E-2 inhibitor.
  • PI3K phosphatidylinositol 3 -kinase
  • the second kinase inhibitor inhibits kinase activity of two or more of kinases, wherein the kinase is selected from the group consisting of VEGFR-l, VEGFR- 2, VEGFR-3, EGFR, ErbB2, ErbB3, ErbB4, class 1 phosphatidylinositol 3-kinase (PI3K), class 2 PI3K, class 3 PI3K, Bcr-Abl tyrosine-kinase, PDGFR, Raf, and ⁇ E-2.
  • PI3K phosphatidylinositol 3-kinase
  • PDGFR phosphatidylinositol 3-kinase
  • Raf Raf
  • ⁇ E-2 class 1 phosphatidylinositol 3-kinase
  • the second kinase inhibitor is selected from the group consisting of regorafenib, pegaptanib, sorafenib, CLJDC- 101 , ponatinib, buparsilib, AST-1306, pazopanib, brigatinib, encorafenib, cabozatinib, acalabrutinib, vandetanib, cobimetinib, lenvatinib, binimetinib, ceritinib, dactobsib, pictilisib, aflibercept, pegaptanib, pazopanib, ranibizumab, sunitinib, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the foregoing methods provide a beneficial synergistic effect in the subject.
  • the cancer is colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the ureth
  • FIG. 1A-FIG. 1C show differential viability of A549 cell line after 1 day (24 hours), 2 days (48 hours), and 3 days (72 hours) treatment of individual inhibitor including Erlotinib, AST- 1306, CUDC-101, Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, 10mM).
  • FIG. 1A represents 1 day treatment
  • FIG. 1B represents 2 days treatment
  • FIG. 1C represents 3 days treatment.
  • FIG. 2A-FIG. 2C show differential viability of ADS 12 cell line after 1 day (24 hours), 2 days (48 hours), and 3 days (72 hours) treatment of individual inhibitor including Erlotinib, AST- 1306, CUDC-101, Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, 10mM).
  • FIG. 2A represents 1 day treatment
  • FIG. 2B represents 2 days treatment
  • FIG. 2C represents 3 days treatment.
  • FIG. 3A-FIG. 3C show differential viability of AsPC-l cell line after 1 day (24 hours), 2 days (48 hours), and 3 days (72 hours) treatment of individual inhibitor including Erlotinib, AST- 1306, CUDC-101, Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, IOmM).
  • FIG. 3A represents 1 day treatment
  • FIG. 3B represents 2 days treatment
  • FIG. 3C represents 3 days treatment.
  • FIG. 4A-FIG. 4C show differential viability of HCT116 cell line after 1 day (24 hours), 2 days (48 hours), and 3 days (72 hours) treatment of individual inhibitor including Erlotinib, AST-1306, CUDC-101, Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, 10mM).
  • FIG. 4A represents 1 day treatment
  • FIG. 4B represents 2 days treatment
  • FIG. 4C represents 3 days treatment.
  • FIG. 5A- FIG. 5C show differential viability of Hep3B cell line after 1 day (24 hours), 2 days (48 hours), and 3 days (72 hours) treatment of individual inhibitor including Erlotinib, AST- 1306, CUDC- 101 , Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, 10mM).
  • FIG. 5 A represents 1 day treatment
  • FIG. 5B represents 2 days treatment
  • FIG. 5C represents 3 days treatment.
  • FIG. 6A-FIG. 6B show differential viability of FIT-29 cell line after 1 day (24 hours) and 2 days (48 hours) treatment of individual inhibitor including Erlotinib, AST-1306, CUDC-101, Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, 10mM).
  • FIG. 6A represents 1 day treatment and
  • FIG. 6B represents 2 days treatment.
  • FIG. 7A-FIG. 7C show differential viability of MeWo cell line after 1 day (24 hours), 2 days (48 hours), and 3 days (72 hours) treatment of individual inhibitor including Erlotinib, AST- 1306, CUDC-101, Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, 10mM).
  • FIG. 7A represents 1 day treatment
  • FIG. 7B represents 2 days treatment
  • FIG. 7C represents 3 days treatment.
  • FIG. 8A-FIG. 8C show differential viability of PANC-l cell line after 1 day (24 hours), 2 days (48 hours), and 3 days (72 hours) treatment of individual inhibitor including Erlotinib, AST-1306, CUDC-101, Buparlisib and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, 10mM).
  • FIG. 8A represents 1 day treatment
  • FIG. 8B represents 2 days treatment
  • FIG. 8C represents 3 days treatment.
  • FIG. 9A shows differential viability of A549 cell line after 3 days co-treatment of Erlotinib and Regorafenib.
  • Erlotinib Various concentrations of Erlotinib were used, including 1.25mM (“Regor+Erl- 1.25”), 2.5mM (“Regor+Erl-2.5”), 5mM (“Regor+Erl-5”), and 10mM (“Regor+Erl- 10”).
  • Various concentrations of Regorafenib were used, including 0.31, 0.62, 1.25, 2.5, 5, or 10mM. The cells were treated with Erlotinib alone for 3 days and with Regorafenib alone for 3 days were included as control.
  • FIG. 9B shows differential viability of AsPC-l cell line after 3 days co-treatment of Erlotinib and Regorafenib.
  • Erlotinib Various concentrations of Erlotinib were used, including 1.25mM (“Regor+Erl- 1.25”), 2.5mM (“Regor+Erl-2.5”), 5mM (“Regor+Erl-5”), and IOmM (“Regor+Erl- 10”).
  • Various concentrations of Regorafenib were used, including 0.31, 0.62, 1.25, 2.5, 5, or 10mM. The cells were treated with Erlotinib alone for 3 days and with Regorafenib alone for 3 days were included as control.
  • FIG. 9C shows differential viability of HCT116 cell line after 3 days co-treatment of Erlotinib and Regorafenib.
  • Erlotinib Various concentrations of Erlotinib were used, including 1.25mM (“Regor+Erl- 1.25”), 2.5mM (“Regor+Erl-2.5”), 5mM (“Regor+Erl-5”), and 10mM (“Regor+Erl- 10”).
  • Various concentrations of Regorafenib were used, including 0.31, 0.62, 1.25, 2.5, 5, or 10mM. The cells were treated with Erlotinib alone for 3 days and with Regorafenib alone for 3 days were included as control.
  • FIG. 9D shows differential viability of Hep3B cell line after 3 days co-treatment of Erlotinib and Regorafenib.
  • Erlotinib Various concentrations of Erlotinib were used, including 1.25mM (“Regor+Erl- 1.25”), 2.5mM (“Regor+Erl-2.5”), 5mM (“Regor+Erl-5”), and 10mM (“Regor+Erl- 10”).
  • Various concentrations of Regorafenib were used, including 0.31, 0.62, 1.25, 2.5, 5, or 10mM. The cells were treated with Erlotinib alone for 3 days and with Regorafenib alone for 3 days were included as control.
  • FIG. 9E shows differential viability of HT-29 cell line after 3 days co-treatment of Erlotinib and Regorafenib.
  • Erlotinib Various concentrations of Erlotinib were used, including 1.25mM (“Regor+Erl- 1.25”), 2.5mM (“Regor+Erl-2.5”), 5mM (“Regor+Erl-5”), and 10mM (“Regor+Erl- 10”).
  • Various concentrations of Regorafenib were used, including 0.31, 0.62, 1.25, 2.5, 5, or 10mM.
  • the cells were treated with Erlotinib alone for 3 days and with Regorafenib alone for 3 days were included as control.
  • FIG. 9F shows differential viability of MeWo cell line after 3 days co-treatment of Erlotinib and Regorafenib.
  • Erlotinib Various concentrations of Erlotinib were used, including 1.25mM (“Regor+Erl- 1.25”), 2.5mM (“Regor+Erl-2.5”), 5mM (“Regor+Erl-5”), and 10mM (“Regor+Erl- 10”).
  • Various concentrations of Regorafenib were used, including 0.31, 0.62, 1.25, 2.5, 5, or 10mM. The cells were treated with Erlotinib alone for 3 days and with Regorafenib alone for 3 days were included as control.
  • FIG. 9G shows differential viability of PANC-l cell line after 3 days co-treatment of Erlotinib and Regorafenib.
  • Erlotinib Various concentrations of Erlotinib were used, including 1.25mM (“Regor+Erl- 1.25”), 2.5mM (“Regor+Erl-2.5”), 5mM (“Regor+Erl-5”), and IOmM (“Regor+Erl- 10”).
  • Various concentrations of Regorafenib were used, including 0.31, 0.62, 1.25, 2.5, 5, or 10mM. The cells were treated with Erlotinib alone for 3 days and with Regorafenib alone for 3 days were included as control.
  • FIG. 10A-FIG. 10G show differential viability of cancer cell lines after 1 day treatment of individual inhibitor at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM) and Erlotinib (10mM), followed by 1 day treatment of Erlotinib (10mM) alone.
  • Individual inhibitor used for 1 day treatment is Erlotinib, AST-1306, CEDC-101, Buparbsib, or Ponatinib.
  • the treated cancer cell lines are A549 (FIG. 10A), ADS 12 (FIG. 10B), AsPC-l (FIG. 10C), Hep3B (FIG. 10D), HT-29 (FIG. 10E), MeWo (FIG. 1 OF), PANC-l (FIG. 10G).
  • FIG. 11A-FIG. 11D show differential viability of cancer cell lines after 3 days pretreatment of Erlotinib (5mM). After Erlotinib was washed off, the cancer cell lines received 1 day treatment of individual inhibitor including AST- 1306 and Ponatinib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM). The viability of the cancer cell lines after 3 days and 4 days of Erlotinib (5mM) were included as control.
  • the treated cancer cell lines were ADS 12 (FIG. 11 A), AsPC-l (FIG. 11B), Hep3B (FIG. 11C), and HT-29 (FIG. 11D).
  • FIG. 12A shows differential viability of A549 cell line after 1 day treatment of individual inhibitor including AST-1306, CUDC-101, Buparbsib, and Ponatinib, at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM).
  • FIG. 12B shows differential viability of A549 cell line after 3 days pretreatment of Erlotinib (10mM) followed by 1 day treatment of individual inhibitor including AST-1306, CUDC- 101, Buparbsib, Ponatinib, and Regorafenib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM). The viability of the cancer cell line after 3 days of Erlotinib (10mM) were included as control.
  • FIG. 13A shows differential viability of AsPC-l cell line after 1 day treatment of individual inhibitor including AST-1306, CUDC-101, Buparbsib, and Ponatinib, at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM).
  • FIG. 13B shows differential viability of AsPC-l cell line after 3 days pretreatment of Erlotinib (IOmM) followed by 1 day treatment of individual inhibitor including AST-1306, CUDC- 101, Buparbsib, Ponatinib, and Regorafenib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM). The viability of the cancer cell line after 3 days of Erlotinib (10mM) were included as control.
  • FIG. 14A shows differential viability of Hep3B cell line after 1 day treatment of individual inhibitor including AST-1306, CUDC-101, Buparbsib, and Ponatinib, at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM).
  • FIG. 14B shows differential viability of Hep3B cell line after 2 days pretreatment of Erlotinib (10mM) followed by 1 day treatment of individual inhibitor including AST-1306, CUDC- 101, Buparbsib, Ponatinib, and Regorafenib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM). The viability of the cancer cell line after 3 days of Erlotinib (10mM) were included as control.
  • FIG. 15 A shows differential viability of MeWo cell line after 1 day treatment of individual inhibitor including AST-1306, CUDC-101, Buparbsib, at Ponatinib, at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM).
  • FIG. 15B shows differential sensitivity and/or viability of MeWo cell line after 3 days pretreatment of Erlotinib (10mM) followed by 1 day treatment of individual inhibitor including AST-1306, CEDC-101, Buparbsib, Ponatinib, and Regorafenib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM).
  • individual inhibitor including AST-1306, CEDC-101, Buparbsib, Ponatinib, and Regorafenib at various concentrations (0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM).
  • the viability of the cancer cell line after 3 days of Erlotinib (10mM) were included as control.
  • FIG. 16A shows differential viability of SK-N-SH cell line after (1) 3 days pretreatment of Erlotinib (“preErl-3d-Buparbsib-3d”); (2) 3 days pretreatment of Erlotinib (10mM) followed by 3 days treatment of Buparbsib (“preErl-3d+Buparlisib-3d”); (3) 6 days treatment of Buparbsib (“Buparbsib-6d’); (4) 6 days co-treatment of Erlotinib and Buparbsib (“Buparlisib+Erl-6d”); (5) 3 days pretreatment of Erlotinib (5mM) followed by 3 days treatment of Buparbsib (“preErl-3d- 5uMTBuparlisib-3d”); or (6) 6 days treatment of Erlotinib (5mM) (“Erl-5uM-6d’).
  • the concentrations of the Buparbsib were 0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM.
  • FIG. 16B shows differential viability of SK-N-SH cell line after (1) 3 days pretreatment of Erlotinib (“preErl-3d-CUDC-l0l-3d”); (2) 3 days pretreatment of Erlotinib (10mM) followed by 3 days treatment of CUDC-101 (“preErl-3d+CUDC-l0l-3d”); (3) 6 days treatment of CUDC-101 (“CUDC-l0l-6d’); (4) 6 days co-treatment of Erlotimb and CUDC-101 (“CUDC-l0l+Erl-6d”); (5) 3 days pretreatment of Erlotinib (5mM) followed by 3 days treatment of CUDC-101 (“preErl-3d- 5uM+ CUDC-l0l3d”); or (6) 6 days treatment of Erlotinib (5mM) (“Erl-5uM-6d’).
  • the concentrations of the CUDC-101 were 0, 0.31, 0.62, 1.25, 2.5, 5, or IOmM.
  • FIG. 17A shows differential viability of IMR-32 cell line after (1) 3 days pretreatment of Erlotinib (“preErl-3d-Buparlisib-3d”); (2) 3 days pretreatment of Erlotinib (10mM) followed by 3 days treatment of Buparlisib (“preErl-3d+Buparlisib-3d”); (3) 6 days treatment of Buparlisib (“Buparlisib-6d’); (4) 6 days co-treatment of Erlotinib and Buparlisib (“Buparlisib+Erl-6d”); or (5) 3 days pretreatment of Erlotinib (5mM) followed by 3 days treatment of Buparlisib (“preErl-3d- 5uM+Buparlisib-3d”).
  • the concentrations of the Buparlisib were 0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM.
  • FIG. 17B shows differential viability of IMR-32 cell line after (1) 3 days pretreatment of Erlotinib (“preErl-3d-CUDC-l0l-3d”); (2) 3 days pretreatment of Erlotinib (10mM) followed by 3 days treatment of CUDC-101 (“preErl-3d+CUDC-l0l-3d”); (3) 6 days treatment of CUDC-101 (“CUDC-l0l-6d’); (4) 6 days co-treatment of Erlotinib and CUDC-101 (“CUDC-l0l+Erl-6d”); (5) 3 days pretreatment of Erlotinib (5mM) followed by 3 days treatment of CUDC-101 (“preErl-3d- 5uM+ CUDC-l0l3d”); (6) 6 days treatment of Erlotinib (5mM) (“Erl-5uM-6d’); or (7) 6 days treatment of Erlotinib (10mM) (“Erl-l0uM-6d’).
  • FIG. 18A shows differential viability of A549 cell line after 3 days pretreatment of Erlotinib (10mM) followed by 1 day treatment of Regorafenib at 0, 0.31, 0.62, 1.25, or 2.5 mM
  • preErl-3d+ Regorafenib- ld 4 days of Erlotinib treatment at 0, 0.31, 0.62, 1.25, or 2.5 mM
  • FIG. 18B shows differential viability of MeWo cell line after 3 days pretreatment of Erlotinib (10mM) followed by 1 day treatment of Regorafenib at 0, 0.31, 0.62, 1.25, or 2.5 mM
  • preErl-3d+ Regorafenib- ld 4 days of Erlotinib treatment at 0, 0.31, 0.62, 1.25, or 2.5 mM
  • FIG. 18C shows differential viability of PANC-l cell line after 3 days pretreatment of Erlotinib (10mM) followed by 1 day treatment of Regorafenib at 0, 0.31, 0.62, 1.25, or 2.5 mM (“preErl-3d+ Regorafenib-ld”). 4 days of Erlotinib treatment at 0, 0.31, 0.62, 1.25, or 2.5 mM (“Erlotinib-4d”) and 4 days of Regorafenib treatment at 0, 0.31, 0.62, 1.25, or 2.5 mM (“Regorafenib-4d”) were included as control.
  • the term“effective amount” means the amount of the subject compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the present disclosure derives from research that provided methods for determining which tumors will respond most effectively to treatment with kinase inhibitors (for example, Thompson, S. et al. (2005) Cancer Res. 65(20):9455-9462).
  • the term“about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication.
  • the language“about 50” means from 45 to 55.
  • the term“subject,” as used herein unless otherwise defined, is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the subject is a human.
  • the subject is an adult human.
  • the subject is a pediatric human.
  • the term“adult human” refers to a human that is 18 years or older.
  • the term“pediatric human” refers to a human that is 1 year to 18 years old.
  • Tumor growth is used as commonly used in oncology, where the term is principally associated with an increased mass or volume of the tumor or tumor metastases, primarily as a result of tumor cell growth.
  • EGFR inhibitor or“EGFR kinase inhibitor” or“EGFR tyrosine kinase inhibitor” or refers to a substance that blocks the activity of a protein called epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • EGFR is found on the surface of some normal cells and is involved in cell growth. It may also be found at high levels on some types of cancer cells, which causes these cells to grow and divide.
  • “EGFR” may refer to any of the members of the EGFR family, which includes EGFR (ErbB-l), HER2/neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4).
  • An EGFR inhibitor can be a small molecule, anti-EGFR antibody, or peptide that inhibits or suppresses EGFR activity.
  • EGFR inhibitors used to treat cancer, including erlotinib (EGFR inhibitor), gefitinib (EGFR inhibitor), icotinib (EGFR inhibitor), lapatinib (dual HER2/EGFR inhibitor), neratinib (dual HER2/EGFR inhibitor), vandetanib (dual VEGFR/EGFR inhibitor), BIBW 2992 (dual HER2/EGFR inhibitor) and XL-647 (triple HER2/EGFR/VEGF inhibitor); as well as monoclonal antibodies, including cetuximab, panitumumab, zalutumumab, nimotuzumab necitumumab, and matuzumab.
  • monoclonal antibodies including cetuximab, panitumumab, zalutumumab, nimotuzumab necitumumab, and matuzumab.
  • the EGFR inhibitor is selected from erlotinib, gefitinib, icotinib, lapatinib, afatinib, neratinib, vandetanib, and tesevatinib.
  • Erlotinib is also known as TARCEVA® and OSI-744, and is marketed by Genentech, OSI Pharmaceuticals, and Roche.
  • the terms “erlotinib” and “erlotinib hydrochloride” are used interchangeably herein.
  • Erlotinib is known to be a selective epidermal growth factor (EGFR)-tyrosine kinase inhibitor.
  • EGFR epidermal growth factor
  • Erlotinib is indicated for the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
  • Erlotinib is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. It has the structure of:
  • Gefitinib is also known as ZD1839. Gefitinib is marketed by AstraZeneca as IRES S A®. Gefitinib reversibly inhibits the kinase activity of wild- type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking EGFR- dependent proliferation. Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR.
  • Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.
  • Gefitinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved. It has the structure of:
  • Icotinib is also known as BPI-2009H. Icotinib is marketed by BetaPharma as CONMANA®. The terms“icotinib” and“icotinib hydrochloride” are used interchangeably herein. Icotinib is a quinazoline derivative that binds reversibly to the ATP binding site of the EGFR protein, preventing completion of the signal transduction cascade. Icotinib is approved for the treatment for EGFR mutation-positive, advanced or metastatic non-small cell lung cancer (NSCLC). Upon initial approval, icotinib was indicated as a second-line or third-line treatment for patients who have failed at least one prior treatment with platinum-based chemotherapy. Icotinib was later approved to treat NSCLC patients with EGFR mutation regardless of past chemotherapy use. It has the structure of:
  • Lapatinib is marketed by GlaxoSmithKline as TYKERB®.
  • the terms“lapatinib” and“lapatinib ditosylate” are used interchangeably herein.
  • Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbBl]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated Ki app values of 3nM and 13hM, respectively) with a dissociation half-life greater than or equal to 300 minutes.
  • EGFR [ErbBl] Epidermal Growth Factor Receptor
  • HER2 [ErbB2] Human Epidermal Receptor Type 2
  • Lapatinib is indicated in combination with: (1) capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab; or (2) letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated. It has the structure of:
  • Afatinib is also known as BIBW-2992. Afatinib is marketed by Boehringer Ingelheim as GILOTRIF®. Afatinib covalently binds to the kinase domains of EGFR (ErbBl), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling.
  • Afatinib is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. It has the structure of:
  • Neratinib is also known as HKI-272. Neratinib is marketed by Puma Biotechnology, Inc. as NERLYNX®. Neratinib is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. Neratinib is indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab- based therapy It has the structure of:
  • Vandetanib is marketed by AstraZeneca as CAPRELSA®. In vitro studies have shown that vandetanib inhibits the tyrosine kinase activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families. In addition, the N- desmethyl metabolite of the drug, representing 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-l) and EGFR.
  • CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. It has the structure of:
  • Tesevatinib is also known as KD019 and XL-647.
  • Kadmon is conducting ongoing Phase 2 clinical trials of tesevatinib for the treatment of EGFR-mutation-positive NSCLC that has metastasized to the brain and/or the leptomeninges (membranes lining the brain and spinal cord) and for the treatment of glioblastoma.
  • Kadmon is also developing tesevatinib for the treatment of autosomal dominant polycystic kidney disease (ADPKD). It has the structure of:
  • EGFRIs epidermal growth factor receptor inhibitors
  • mAb monoclonal antibodies
  • mAb monoclonal antibodies
  • cetuximab panitumumab, necitumumab, zalutumumab
  • These anti-EGFR antibodies are desirable candidates as the first kinase inhibitor since they were known to the target-specific.
  • Sorafenib is also known as NEXAVAR®, and is marketed by Bayer and Onyx Pharmaceuticsl.
  • the terms“sorafenib” and“sorafenib tosylate” are used interchangeably herein.
  • Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-l, VEGFR-2, VEGFR-3, and PDGFR-B).
  • Sorafenib inhibited tumor growth and angiogenesis of human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice. Sorafenib is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and for the treatment of patients with advanced renal cell carcinoma (RCC). It has the structure of:
  • Regorafenib is also known as STIVARGA® and is an analog of sorafenib marketed by Bayer. Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.
  • regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-l, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically.
  • regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.
  • Regorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti- VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. It has the structure of:
  • Pegaptanib is also known as MACUGEN® and is marketed by OSI Pharmaceuticals.
  • the terms“pegaptanib” and“sodium pegaptanib” are used interchangeably herein.
  • Pegaptanib is an aptamer, a pegylated modified oligonucleotide, which adopts a threedimensional conformation that enables it to bind to extracellular VEGF. Linder in vitro testing conditions, pegaptanib binds to the major pathological VEGF isoform, extracellular VEGF 165, thereby inhibiting VEGF 165 binding to its VEGF receptors.
  • VEGF 164 the rodent counterpart of human VEGF 165
  • Pegaptanib is indicated for the treatment of neovascular (wet) age-related macular degeneration. It has the structure of:
  • CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HD AC) with preclinical activity in head and neck squamous cell cancer (HNSCC).
  • EGFR epidermal growth factor receptor
  • HER2 human growth factor receptor 2
  • HD AC histone deacetylase
  • CUDC-101 has been evaluated as an addition to standard concurrent cisplatin-radiotherapy in the treatment of head and neck squamous cell cancer (HNSCC). It has the structure of:
  • Ponatinib is also known as ICLUSIG® and AP24534, and is marketed by ARIAD Pharmaceuticals.
  • Ponatinib is a kinase inhibitor that inhibits the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively.
  • Ponatinib inhibits the in vitro activity of additional kinases with ICso concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, ⁇ E2, and FLT3.
  • Ponatinib inhibits the in vitro viability of cells expressing native or mutant BCR- ABL, including T315I. In mice, treatment with ponatinib reduces the size of tumors expressing native or T315I mutant BCR- ABL when compared to controls.
  • Ponatinib is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. It has the structure of:
  • Buparsilib is also known as BM120, and is an investigational small molecule orally-available pan-class I phosphoinositide 3 -kinase inhibitor. Buparlisib has been evaluated for activity in patients with metastatic estrogen receptor (ER)-positive breast cancer or non-small cell lung cancer (NSCLC). It has the structure of:
  • AST-1306 is also known as“allitinib” or“AST1306,” and is made by Shanghai
  • AST-1306 is a potent, selective, irreversible ErbB2 and EGFR inhibitor. AST-1306 inhibits the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. AST- 1306 is found to function as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively.
  • EGFR epidermal growth factor receptor
  • AST1306 potently suppresses tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu) transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts.
  • AST-1306 has been evaluated for use in patients with advanced solid tumors. It has the structure of:
  • Pazopanib is also known as VOTRIENT®, and is marketed by Novartis.
  • the terms“pazopanib” and“pazopanib hydrochloride” are used interchangeably herein.
  • Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-a and -b, fibroblast growth factor receptor (FGFR)-l and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).
  • VEGFR vascular endothelial growth factor receptor
  • VEGFR-2 VEGFR-2
  • VEGFR-3 platelet-derived growth
  • pazopanib inhibites ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-b receptors.
  • pazopanib inhibites VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice.
  • Pazopanib is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) and for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. It has the structure of:
  • the present disclosure provides methods for treating a subject having cancer, which comprises (a) administering to the subject an effective amount of a first kinase inhibitor; and (b) administering to the subject an effective amount of a second kinase inhibitor.
  • the first kinase inhibitor is administered before or concurrently with the second kinase inhibitor.
  • the present invention further provides methods of treating a subject having cancer, which comprises (a) sensitizing cells of the cancer to a second kinase inhibitor by administering to the subject an effective amount of a first kinase inhibitor; (b) thereafter administering an effective amount of the second kinase to the subject.
  • the first kinase inhibitor is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days before the second kinase inhibitor is administered to the subject. In certain embodiments, wherein the first kinase inhibitor is administered at least 1 to 96 hours before the second kinase inhibitor is administered to the subject.
  • the first kinase inhibitor is an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of erlotinib, gefitinib, icotinib, lapatinib, afatinib, neratinib, vandetanib, pelitinib, canertinib dacomitinib, BIBW 2992, and XL-647, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the EGFR inhibitor is selected from the group consisting of cetuximab, zalutumumab, or panitumumab, nimotuzumab, necitumumab, and matuzumab, and any combination thereof.
  • the EGFR inhibitor is administered at a dose of about 25 to about 1000 mg/m 2 .
  • the EGFR inhibitor is administered once a week.
  • the EGFR inhibitor is administered every two weeks.
  • the EGFR inhibitor is administered every three weeks.
  • the EGFR inhibitor is administered every four weeks.
  • the first kinase inhibitor is a specific EGFR inhibitor.
  • the EGFR inhibitor is erlotinib, and erlotinib is administered at a dose of about 25 to about 2000 mg/day. In certain embodiments, erlotinib is administered at a dose of 25,
  • the forgoing methods further comprise administering to the subject an effective amount of an agent that increases the rate of metabolism of erlotinib by the patient, to treat the cancer.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450. In certain embodiments, the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of cytochrome P450 3A4.
  • the agent that increases the rate of metabolism of erlotinib is selected from the group consisting of a corticosteroid, nicotine, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the agent that increases the rate of metabolism of erlotinib is selected from the group consisting of nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John’s wort, sulfadimidine, sulfinpyrazone, troglitazone, a pharmaceutically acceptable salt of any of the foregoing,
  • the agent that increases the rate of metabolism of erlotinib is administered to the patient in an amount that increases the rate of metabolism of erlotinib by the patient by at least 15%. In certain embodiments, the agent that increases the rate of metabolism of erlotinib is administered to the patient in an amount that increases the rate of metabolism of erlotinib by the patient by at least 25%. In certain embodiments, the agent that increases the rate of metabolism of erlotinib is administered to the patient in an amount that increases the rate of metabolism of erlotinib by the patient by at least 50%.
  • the second kinase inhibitor is a VEGFR-l inhibitor, VEGFR- 2 inhibitor, VEGFR-3 inhibitor, EGFR inhibitor, ErbB2 inhibitor, ErbB3 inhibitor, ErbB4 inhibitor, class 1 phosphatidylinositol 3 -kinase (PI3K) inhibitor, class 2 PI3K inhibitor, class 3 PI3K inhibitor, Bcr-Abl tyrosine-kinase inhibitor, PDGFR inhibitor, Raf inhibitor, and/or ⁇ E-2 inhibitor.
  • PI3K phosphatidylinositol 3 -kinase
  • the second kinase inhibitor inhibits kinase activity of two or more of kinases, wherein the kinase is selected from the group consisting of VEGFR-l, VEGFR- 2, VEGFR-3, EGFR, ErbB2, ErbB3, ErbB4, class 1 phosphatidylinositol 3-kinase (PI3K), class 2 PI3K, class 3 PI3K, Bcr-Abl tyrosine-kinase, PDGFR, Raf, and TIE-2.
  • PI3K phosphatidylinositol 3-kinase
  • the second kinase inhibitor inhibits kinase activity of three or more of kinases, wherein the kinase is selected from the group consisting of VEGFR-l, VEGFR-2, VEGFR-3, EGFR, ErbB2, ErbB3, ErbB4, class 1 phosphatidylinositol 3-kinase (PI3K), class 2 PI3K, class 3 PI3K, Bcr-Abl tyrosine-kinase, PDGFR, Raf, and ⁇ E-2.
  • PI3K phosphatidylinositol 3-kinase
  • the second kinase inhibitor is selected from the group consisting of regorafenib, pegaptanib, sorafenib, CUDC-101 , ponatinib, buparsilib, AST-1306, pazopanib, brigatinib, encorafenib, cabozatinib, acalabrutinib, vandetanib, cobimetinib, lenvatinib, binimetinib, ceritinib, dactobsib, pictilisib, aflibercept, pegaptanib, pazopanib, ranibizumab, sunitinib, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the second kinase inhibitor is regorafenib, and regorafenib is administered at a dose of about 40 to about 500 mg/day.
  • regorafenib is administered at a dose of 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg/day.
  • the second kinase inhibitor is pegaptanib
  • pegaptanib is administered at a dose of about 10 to about 160 mg/kg/day.
  • pegaptanib is administered at a dose of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, or 160 mg/kg/day.
  • the second kinase inhibitor is sorafenib, and sorafenib is administered at a dose of about 100 to about 2000 mg/day. In certain embodiments, sorafenib is administered at a dose of 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425,
  • sorafenib is administered at a dose of about 100 to about 2000 mg every other day. In certain embodiments, sorafenib is administered at a dose of 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650,
  • the second kinase inhibitor is CLJDC- 101
  • CUDC-101 is administered at a dose of about 100 to about 400 mg/m 2 .
  • CUDC-101 is administered at a dose of 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg/m 2 .
  • CUDC-101 is administered three times per week.
  • the second kinase inhibitor is ponatinib, and ponatinib is administered at a dose of about 20 to about 100 mg/day. In certain embodiments, ponatinib is administered at a dose of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/day.
  • the second kinase inhibitor is buparsilib, and buparsilib is administered at a dose of about 40 to about 200 mg/day.
  • buparsilib is administered at a dose of 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg/day.
  • the second kinase inhibitor is AST-1306, and AST-1306 is administered at a dose of about 100 to about 2000 mg/day. In certain embodiments, AST-1306 is administered at a dose of 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425,
  • the second kinase inhibitor is pazopanib
  • pazopanib is administered at a dose of about 50 to about 1600 mg/day.
  • pazopanib is administered at a dose of 50, 60, 70, 80, 90 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,
  • the foregoing methods provide a beneficial synergistic effect in the subject.
  • the cancer is colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ure
  • the subject has been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and/or an anti-EGFR therapy.
  • the present disclosure provides methods of sensitizing cells of a cancer in a subject having the cancer to a second kinase inhibitor, which comprises administering to the subject an effective amount of a first kinase inhibitor.
  • the present disclosure further provides methods for sensitizing a solid tumor or hematologic tumor in a subject to a second kinase inhibitor, which comprises (a) administering to the subject an effective amount of a first kinase inhibitor; and (b) administering to the subject an effective amount of the second kinase inhibitor.
  • the administration of the first kinase inhibitor affects the pharmacokinetics and/or tolerability of a second kinase inhibitor in the subject.
  • the combination of the first kinase inhibitor and the second kinase inhibitor is sufficient to inhibit activity in cells required for growth of the solid or hematologic tumors, and wherein the cells are selected from the group consisting of cancer cells, cancer stem cells, stromal cells, and endothelial cells.
  • the solid tumor or hematologic tumor is resistant to the antitumor activity of the first kinase inhibitor and/or the second kinase inhibitor.
  • the first kinase inhibitor is administered before or concurrently with the second kinase inhibitor. In certain embodiments, the first kinase inhibitor is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days before the second kinase inhibitor is administered to the subject. In certain embodiments, wherein the first kinase inhibitor is administered at least 1 to 96 hours before the second kinase inhibitor is administered to the subject.
  • the first kinase inhibitor is an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of erlotinib, gefitinib, icotinib, lapatinib, afatinib, neratinib, vandetanib, pelitinib, canertinib dacomitinib, BIBW 2992, and XL-647, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the EGFR inhibitor is selected from the group consisting of cetuximab, zalutumumab, or panitumumab, nimotuzumab, necitumumab, and matuzumab, and any combination thereof.
  • the EGFR inhibitor is administered at a dose of about 25 to about 1000 mg/m 2 .
  • the EGFR inhibitor is administered once a week.
  • the EGFR inhibitor is administered every two weeks.
  • the EGFR inhibitor is administered every three weeks.
  • the EGFR inhibitor is administered every four weeks.
  • the first kinase inhibitor is a specific EGFR inhibitor.
  • the EGFR inhibitor is erlotinib, and erlotinib is administered at a dose of about 25 to about 2000 mg/day. In certain embodiments, erlotinib is administered at a dose of 25,
  • the forgoing methods further comprise administering to the subject an effective amount of an agent that increases the rate of metabolism of erlotinib by the patient, to treat the cancer.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of a cytochrome P450.
  • the agent that increases the rate of metabolism of erlotinib is an agent that increases the activity of cytochrome P450 3A4.
  • the agent that increases the rate of metabolism of erlotinib is selected from the group consisting of a corticosteroid, nicotine, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the agent that increases the rate of metabolism of erlotinib is selected from the group consisting of nicotine, carbamazepine, dexamethasone, ethosuximide, a glucocorticoid, griseofulvin, phenytoin, primidone, progesterone, rifabutin, rifampin, nafcillin, nelfinavir, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, rofecoxib, St. John’s wort, sulfadimidine, sulfinpyrazone, troglitazone, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the agent that increases the rate of metabolism of erlotinib is administered to the patient in an amount that increases the rate of metabolism of erlotinib by the patient by at least 15%. In certain embodiments, the agent that increases the rate of metabolism of erlotinib is administered to the patient in an amount that increases the rate of metabolism of erlotinib by the patient by at least 25%. In certain embodiments, the agent that increases the rate of metabolism of erlotinib is administered to the patient in an amount that increases the rate of metabolism of erlotinib by the patient by at least 50%.
  • the second kinase inhibitor is a VEGFR-l inhibitor, VEGFR- 2 inhibitor, VEGFR-3 inhibitor, EGFR inhibitor, ErbB2 inhibitor, ErbB3 inhibitor, ErbB4 inhibitor, class 1 phosphatidylinositol 3 -kinase (PI3K) inhibitor, class 2 PI3K inhibitor, class 3 PI3K inhibitor, Bcr-Abl tyrosine-kinase inhibitor, PDGFR inhibitor, Raf inhibitor, and/or ⁇ E-2 inhibitor.
  • PI3K phosphatidylinositol 3 -kinase
  • the second kinase inhibitor inhibits kinase activity of two or more of kinases, wherein the kinase is selected from the group consisting of VEGFR-l, VEGFR- 2, VEGFR-3, EGFR, ErbB2, ErbB3, ErbB4, class 1 phosphatidylinositol 3-kinase (PI3K), class 2 PI3K, class 3 PI3K, Bcr-Abl tyrosine-kinase, PDGFR, Raf, and TIE-2.
  • PI3K phosphatidylinositol 3-kinase
  • the second kinase inhibitor inhibits kinase activity of three or more of kinases, wherein the kinase is selected from the group consisting of VEGFR-l, VEGFR-2, VEGFR-3, EGFR, ErbB2, ErbB3, ErbB4, class 1 phosphatidylinositol 3-kinase (PI3K), class 2 PI3K, class 3 PI3K, Bcr-Abl tyrosine-kinase, PDGFR, Raf, and TIE-2.
  • PI3K phosphatidylinositol 3-kinase
  • the second kinase inhibitor is selected from the group consisting of regorafenib, pegaptanib, sorafenib, CFDC-101, ponatinib, buparsilib, AST-1306, pazopanib, brigatinib, encorafenib, cabozatinib, acalabrutinib, vandetanib, cobimetinib, lenvatinib, binimetinib, ceritinib, dactolisib, pictilisib, aflibercept, pegaptanib, pazopanib, ranibizumab, sunitinib, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the second kinase inhibitor is regorafenib, and regorafenib is administered at a dose of about 40 to about 500 mg/day. In certain embodiments, regorafenib is administered at a dose of 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg/day.
  • the second kinase inhibitor is pegaptanib, and pegaptanib is administered at a dose of about 10 to about 160 mg/kg/day. In certain embodiments, pegaptanib is administered at a dose of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, or 160 mg/kg/day.
  • the second kinase inhibitor is sorafenib, and sorafenib is administered at a dose of about 100 to about 2000 mg/day. In certain embodiments, sorafenib is administered at a dose of 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425,
  • sorafenib is administered at a dose of about 100 to about 2000 mg every other day. In certain embodiments, sorafenib is administered at a dose of 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650,
  • the second kinase inhibitor is CUDC-101
  • CUDC-101 is administered at a dose of about 100 to about 400 mg/m 2 .
  • CUDC-101 is administered at a dose of 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg/m 2 .
  • CUDC-101 is administered three times per week.
  • the second kinase inhibitor is ponatinib, and ponatinib is administered at a dose of about 20 to about 100 mg/day. In certain embodiments, ponatinib is administered at a dose of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/day. [00118] In certain embodiments, the second kinase inhibitor is buparsilib, and buparsilib is administered at a dose of about 40 to about 200 mg/day.
  • buparsilib is administered at a dose of 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg/day.
  • the second kinase inhibitor is AST-1306, and AST-1306 is administered at a dose of about 100 to about 2000 mg/day. In certain embodiments, AST-1306 is administered at a dose of 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425,
  • the second kinase inhibitor is pazopanib
  • pazopanib is administered at a dose of about 50 to about 1600 mg/day.
  • pazopanib is administered at a dose of 50, 60, 70, 80, 90 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,
  • the foregoing methods provide a beneficial synergistic effect in the subject.
  • the cancer is colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ure
  • the subject has been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and/or an anti-EGFR therapy.
  • the hematopoietic tumor is leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), e.g., transformed CLL, diffuse large B-cell lymphomas (DLBCL), follicular lymphoma, hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma, non-Hodgkin's lymphoma, Burkitfs lymphoma, multiple myeloma, or Richter’s Syndrome (Richter’s Transformation).
  • ALL acute lymphoblastic leukemia
  • B-cell B-cell
  • T-cell or FAB ALL acute myeloid leukemia
  • AML acute myeloid leukemia
  • CML chronic myelocytic leukemia
  • the solid tumor is sarcomas, adenocarcinomas, and carcinomas, of the various organ systems, such as those affecting head and neck (including pharynx), thyroid, lung (small cell or non-small cell lung carcinoma (NSCLC)), breast, lymphoid, gastrointestinal (e.g., oral, esophageal, stomach, liver, pancreas, small intestine, colon and rectum, anal canal), genitals and genitourinary tract (e.g., renal, urothelial, bladder, ovarian, uterine, cervical, endometrial, prostate, testicular), CNS (e.g., neural or glial cells, e.g., neuroblastoma or glioma), or skin (e.g., melanoma).
  • CNS e.g., neural or glial cells, e.g., neuroblastoma or glioma
  • skin e.g., mela
  • compositions for the treatment of a subject having cancer or preventing the development of a tumor in a subject at risk of developing the tumor comprising (i) a first kinase inhibitor, and (ii) a second kinase inhibitor, and a pharmaceutically acceptable carrier.
  • the first kinase inhibitor is an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of erlotinib, gefitinib, icotinib, lapatinib, afatinib, neratinib, vandetanib, pelitinib, canertinib dacomitinib, BIBW 2992, and XL-647, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the EGFR inhibitor is selected from the group consisting of cetuximab, zalutumumab, or panitumumab, nimotuzumab, necitumumab, and matuzumab, and any combination thereof.
  • the first kinase inhibitor is a specific EGFR inhibitor.
  • the EGFR inhibitor is erlotinib.
  • the second kinase inhibitor is a VEGFR-l inhibitor, VEGFR- 2 inhibitor, VEGFR-3 inhibitor, EGFR inhibitor, ErbB2 inhibitor, ErbB3 inhibitor, ErbB4 inhibitor, class 1 phosphatidylinositol 3 -kinase (PI3K) inhibitor, class 2 PI3K inhibitor, class 3 PI3K inhibitor, Bcr-Abl tyrosine-kinase inhibitor, PDGFR inhibitor, Raf inhibitor, and/or ⁇ E-2 inhibitor.
  • PI3K phosphatidylinositol 3 -kinase
  • the second kinase inhibitor inhibits kinase activity of two or more of kinases, wherein the kinase is selected from the group consisting of VEGFR-l, VEGFR- 2, VEGFR-3, EGFR, ErbB2, ErbB3, ErbB4, class 1 phosphatidylinositol 3-kinase (PI3K), class 2 PI3K, class 3 PI3K, Bcr-Abl tyrosine-kinase, PDGFR, Raf, and TIE-2.
  • PI3K phosphatidylinositol 3-kinase
  • the second kinase inhibitor inhibits kinase activity of three or more of kinases, wherein the kinase is selected from the group consisting of VEGFR-l, VEGFR-2, VEGFR-3, EGFR, ErbB2, ErbB3, ErbB4, class 1 phosphatidylinositol 3-kinase (PI3K), class 2 PI3K, class 3 PI3K, Bcr-Abl tyrosine-kinase, PDGFR, Raf, and TIE-2.
  • PI3K phosphatidylinositol 3-kinase
  • the second kinase inhibitor is selected from the group consisting of regorafenib, pegaptanib, sorafenib, CFDC-101, ponatinib, buparsilib, AST-1306, pazopanib, brigatinib, encorafenib, cabozatinib, acalabrutinib, vandetanib, cobimetinib, lenvatinib, binimetinib, ceritinib, dactobsib, pictilisib, aflibercept, pegaptanib, pazopanib, ranibizumab, sunitinib, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.
  • the pharmaceutical acceptable carrier or vehicle can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when the first kinase inhibitor or the second kinase inhibitor is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained release formulation; (3) topical application, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g.
  • compositions of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, e.g., from about 5 percent to about 70 percent, or from about 10 percent to about 30 percent.
  • a composition of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and the first kinase inhibitor or the second kinase inhibitor.
  • an aforementioned composition renders orally bioavailable the first kinase inhibitor or the second kinase inhibitor.
  • compositions or compositions include the step of bringing into association the first kinase inhibitor or the second kinase inhibitor with the carrier and, optionally, one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association a CETP inhibitor or ADCY inhibitor with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of the first kinase inhibitor or the second kinase inhibitor as an active ingredient.
  • the first kinase inhibitor or the second kinase inhibitor may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the first kinase inhibitor or the second kinase inhibitor include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by admixing one or both of the first kinase inhibitor or the second kinase inhibitor with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray compositions containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of the first kinase inhibitor or the second kinase inhibitor to a subject.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • compositions of this invention suitable for parenteral administration can comprise the first kinase inhibitor, the second kinase inhibitor and one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the composition isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable compositions are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable compositions are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • first kinase inhibitor or the second kinase inhibitor When administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be administered orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and“administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the first kinase inhibitor or the second kinase inhibitor which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically- acceptable dosage forms by conventional methods known to those of skill in the art.
  • compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular first kinase inhibitor or second kinase inhibitor employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian can readily determine and prescribe the effective amount of the pharmaceutical composition. For example, the physician or veterinarian could start doses of the first kinase inhibitor or the second kinase inhibitor employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of the first kinase inhibitor or the second kinase inhibitor is that amount of the first kinase inhibitor or the second kinase inhibitor which is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms, e.g., one administration per day.
  • kits useful for treating or preventing a cardiovascular disorder or reducing risk of a cardiovascular event as described herein.
  • the kits comprise the first kinase inhibitor or the second kinase inhibitor and instructions for its use.
  • each of the first kinase inhibitor or the second kinase inhibitor is present in a separate composition.
  • the first kinase inhibitor and the second kinase inhibitor are present in the same composition.
  • the invention also provides the first kinase inhibitor and the second kinase inhibitor as described herein and compositions comprising an effective amount of the first kinase inhibitor and the second kinase inhibitor as described herein for use in the methods described herein.
  • Example 1 Sensitivity of cancer cell lines to individual kinase inhibitor
  • a single agent selected from Erlotinib, AST-1306, CUDC-101, Buparlisib, and Ponatinib.
  • the cell lines were continuously exposed to varying concentrations of each individual inhibitor for at least 24-72 hours. Cells were harvested at 24, 48, 72 hours after the treatment started.
  • the cell sensitivity/viability response was tested using the MTT assay.
  • the conversion of MTT into formazan by viable cells was assessed by a microplate reader at 570 nm. The results are presented as a percentage of the viability of untreated cells (control), which are regarded as 100 % viable.
  • the MTT assay used in this study was described previously (Ling, Y- H et al., Cancer Res. (1993) 53(7): l583-l 589.)
  • Example 2 Combination effects of Erlotinib and other kinase inhibitors on cancer cells in vitro
  • Example 3 Combination effects of Erlotinib and other kinase inhibitors with sequential treatment on cancer cells in vitro
  • FIG. 11A-FIG. 11D demonstrates differential cell viability and/or sensitivity of the cell lines tested.
  • cancer cells are sensitized by pre-exposure to a selective EGFR inhibitor, such as Erlotinib, to relatively non-selective kinase inhibitors such as AST-1306, CEDC-101, Buparlisib, Ponatinib, and Regorafenib.
  • a selective EGFR inhibitor such as Erlotinib
  • relatively non-selective kinase inhibitors such as AST-1306, CEDC-101, Buparlisib, Ponatinib, and Regorafenib.
  • the combination with a selective EGFR inhibitor enables treatment using relatively non-selective kinase inhibitors at a lower dose to achieve approximately the same or higher tumor-killing effects and lower side effects when compared with monotherapy with the relatively non-selective kinase inhibitors.
  • Example 4 Combination effects of Erlotinib and Buparlisib with sequential and/or concurrent treatment in neuroblastoma cells in vitro
  • SK-N-SH and IMR-32 neuroblastoma cell lines
  • viability of the SK-N-SH cell line was measured after (1) 3 days pretreatment of Erlotinib (“preErl-3d-Buparlisib-3d”); (2) 3 days pretreatment of Erlotinib followed by 3 days treatment of Buparlisib (“preErl-3d+Buparlisib-3d”); (3) 6 days treatment of Buparlisib (“Buparlisib-6d’); (4) 6 days co-treatment of Erlotinib and Buparlisib (“Buparlisib+Erl-6d”); (5) 3 days pretreatment of Erlotinib (5mM) followed by 3 days treatment of Buparlisib (“preErl-3d- 5uM+Buparbsib-3d”); or (6) 6 days treatment of Erlotinib
  • the concentrations of the Buparlisib were 0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM. See FIG. 16A.
  • viability of the IMR-32 cell line after (1) 3 days pretreatment of Erlotinib (“preErl-3d-Buparlisib-3d”); (2) 3 days pretreatment of Erlotinib (IOmM) followed by 3 days treatment of Buparbsib (“preErl-3d+Buparbsib-3d”); (3) 6 days treatment of Buparbsib (“Buparbsib-6d’); (4) 6 days co-treatment of Erlotinib and Buparbsib (“Buparlisib+Erl-6d”); or (5) 3 days pretreatment of Erlotinib (5mM) followed by 3 days treatment of Buparbsib (“preErl-3d- 5uM+Buparbsib-3d”).
  • the concentrations of the Buparbsib were 0, 0.31, 0.62, 1.25, 2.5, 5, or 10mM. See FIG. 17A.
  • Example 5 Combination effects of Erlotinib and CUDC-101 with sequential and/or concurrent treatment in neuroblastoma cells in vitro
  • SK-N-SH and IMR-32 Two neuroblastoma cell lines (SK-N-SH and IMR-32) were selected.
  • viability of the SK-N-SH cell line was measured after (1) 3 days pretreatment of Erlotinib (“preErl-3d-CUDC-l0l-3d”); (2) 3 days pretreatment of Erlotinib (10mM) followed by 3 days treatment of CUDC-101 (“preErl-3d+CUDC-l0l-3d”); (3) 6 days treatment of CUDC-101 (“CUDC-l0l-6d’); (4) 6 days co-treatment of Erlotinib and CUDC-101 (“CUDC-l0l+Erl-6d”); (5) 3 days pretreatment of Erlotinib (5mM) followed by 3 days treatment of CUDC-101 (“preErl-3d- 5uM+ CUDC-l0l3d”); or (6) 6 days treatment of Erlotinib (5
  • CUDC-101 showed 100% killing with 0.3mM alone in the IMR-32 cells as shown in FIG. 17B. However, a relatively low dosage about 0.31 to about 1.25mM of CUDC-101 either when pretreated with Erlotinib for 3 days or given concurrent treatment with Erlotinib was observed with a potent killing of almost all SK-N-SH cells (FIG. 16B). This indicates an effective treatment of CUDC-101 with low dosage in combination with Erlotinib either sequentially or concurrently.
  • Example 6 Combination effects of Erlotinib and Regorafenib on cancer cells in vitro

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  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions et des méthodes utiles pour traiter le cancer et/ou sensibiliser des cellules tumorales à des inhibiteurs de kinases.
PCT/US2019/020550 2018-03-02 2019-03-04 Méthodes et compositions pour traiter le cancer et sensibiliser des cellules tumorales à des inhibiteurs de kinase WO2019169389A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112920193A (zh) * 2021-02-07 2021-06-08 南通大学 一种灰黄霉素四唑衍生物及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5770593A (en) * 1988-08-18 1998-06-23 Boehringer Mannheim Gmbh Method of determining a pharmaceutical combination preparations for use in anti-neoplastic therapy
US20060084691A1 (en) * 2004-10-18 2006-04-20 Bilal Piperdi Combined treatment with bortezomib and an epidermal growth factor receptor kinase inhibitor
US20070099847A1 (en) * 2005-10-28 2007-05-03 The Regents Of The University Of California Tyrosine kinase receptor antagonists and methods of treatment for pancreatic and breast cancer
US20070280928A1 (en) * 2006-03-13 2007-12-06 Buck Elizabeth A Combined treatment with an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors
US20150297590A1 (en) * 2014-04-16 2015-10-22 Signal Pharmaceuticals, Llc Methods for treating cancer using tor kinase inhibitor combination therapy
WO2017127495A1 (fr) * 2016-01-19 2017-07-27 The Johns Hopkins University Sensibilisation d'un cancer à des agonistes des récepteurs de mort cellulaire à l'aide d'inhibiteurs de kinases

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5770593A (en) * 1988-08-18 1998-06-23 Boehringer Mannheim Gmbh Method of determining a pharmaceutical combination preparations for use in anti-neoplastic therapy
US20060084691A1 (en) * 2004-10-18 2006-04-20 Bilal Piperdi Combined treatment with bortezomib and an epidermal growth factor receptor kinase inhibitor
US20070099847A1 (en) * 2005-10-28 2007-05-03 The Regents Of The University Of California Tyrosine kinase receptor antagonists and methods of treatment for pancreatic and breast cancer
US20070280928A1 (en) * 2006-03-13 2007-12-06 Buck Elizabeth A Combined treatment with an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors
US20150297590A1 (en) * 2014-04-16 2015-10-22 Signal Pharmaceuticals, Llc Methods for treating cancer using tor kinase inhibitor combination therapy
WO2017127495A1 (fr) * 2016-01-19 2017-07-27 The Johns Hopkins University Sensibilisation d'un cancer à des agonistes des récepteurs de mort cellulaire à l'aide d'inhibiteurs de kinases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112920193A (zh) * 2021-02-07 2021-06-08 南通大学 一种灰黄霉素四唑衍生物及其制备方法

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