Pharmaceutical combination for treating cancer

Abstract

To provide combination therapies for the treatment of colorectal cancer and familial adenomatous polyposis (TAP).SOLUTION: In one aspect, the present disclosure provides a method of treating cancer, comprising administering a therapeutically effective amount of budesonide or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to a subject in need thereof. In some embodiments, the cancer is selected from colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, and urinary tract epithelial cancer. In some embodiments, the cancer is colorectal cancer.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming the benefit of U.S. Provisional Patent Application No. 62 / 783,911, filed December 21, 2018, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates generally to the fields of medicine, cancer biology and treatment, and in particular to novel drug and drug combination methods and therapeutic strategies for treating cancer, as well as pharmaceutical compositions comprising such combinations and methods of making and using the same. [Background technology]

[0003] Many cancer-related treatments are in Phase I or II clinical trials and evaluation at any particular time, but most of them fail to move forward. In fact, it is estimated that more than 90% of cancer-related therapeutics fail in Phase I or II clinical trial evaluation. The failure rate in Phase III trials is nearly 50%, and the cost of new drug development from discovery to Phase III trials can be between $800 million and $1.7 billion and take 8 to 10 years. In addition, many patients do not respond even to reference drugs that have been shown to be effective. Currently, individual patients may not respond to standard drug treatments for reasons that are not well understood or easily evaluated. In some cases, administration of drug combinations can be more effective for treating cancer than the drugs administered individually. These drug combinations can act synergistically to enhance the anti-cancer activity of the drugs. In some cases, drugs that are not particularly effective may find new and unexpected uses when combined with additional drug treatments.

[0004] Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer-related deaths in the United States, with an estimated 141,000 cases diagnosed in 2011. Although surgical resection of early noninvasive adenomas is curative, patients with advanced CRC have few effective treatment options and often have a poor prognosis. Despite a long latency period, only a small proportion of lesions are identified at a stage that can be surgically removed. Mutations in the human APC tumor suppressor gene are linked to familial adenomatous polyposis (FAP), an inherited cancer-predisposing condition that results in the formation of numerous polyps in the epithelium of the large intestine. The development of CRC begins with the abnormal outgrowth of adenomatous polyps from the colonic epithelium, which eventually progresses to invasive carcinoma. Approximately 85% of sporadic colorectal cancers have been reported to harbor APC truncating mutations. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, the disclosure provides a method of treating cancer, comprising administering a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to a subject in need thereof. In some embodiments, the cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, renal cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheloma, and / or leiomyosarcoma. eliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, throat cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia In some embodiments, the cancer is selected from: nonlymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. In some embodiments, the cancer is selected from: colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, and urothelial cancer. In some embodiments, the cancer is colorectal cancer.

[0006] In one aspect, the disclosure provides a method of treating a condition or disorder in a subject with an APC mutation, comprising administering a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to a subject in need thereof. In some embodiments, the condition or disorder is cancer. In some embodiments, the cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, and gliomas of the head and neck. Cancer, hemangioblastoma, hepatocellular carcinoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retina Selected from blastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, throat cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. In some embodiments, the cancer is selected from colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma and urothelial cancer.In some embodiments, the cancer is colorectal cancer.In some embodiments, the method further comprises diagnosing APC mutation in the subject.

[0007] In another aspect, the disclosure provides a method of treating familial adenomatous polyposis (FAP), comprising administering a therapeutically effective amount of budesonide, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, to a subject in need thereof. In some embodiments, the subject has an APC mutation.

[0008] In another aspect, the disclosure provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a therapeutically effective amount of an additional therapeutic agent or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the therapeutically effective amount of budesonide and the therapeutically effective amount of the additional therapeutic agent are synergistic amounts. In some embodiments, the cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, and gliomas of the head and neck. Cancer, hemangioblastoma, hepatocellular carcinoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retina Selected from blastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, throat cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. In some embodiments, the cancer is selected from colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, and urothelial cancer, hi some embodiments, the cancer is colorectal cancer.In some embodiments, the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. In some embodiments, the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. In some embodiments, the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. In some embodiments, the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the additional therapeutic agent is a statin. In some embodiments, the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. In some embodiments, the additional therapeutic agent is a survivin inhibitor. In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the additional therapeutic agent is a bone morphogenetic protein. In some embodiments, the budesonide and the additional therapeutic agent are administered simultaneously. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 hour to about 24 hours of each other. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 day to about 7 days of each other. In some embodiments, the budesonide and the additional therapeutic agent are formulated together in a pharmaceutical composition.In some embodiments, the budesonide and additional therapeutic agent are administered every day, every second day, or every third day.

[0009] In another aspect, the disclosure provides a method of treating a condition or disorder in a subject having an APC mutation, comprising administering to a subject in need thereof a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a therapeutically effective amount of an additional therapeutic agent or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the therapeutically effective amount of budesonide and the therapeutically effective amount of the additional therapeutic agent are synergistic. In some embodiments, the condition or disorder is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, and gliomas. Neck cancer, hemangioblastoma, hepatocellular carcinoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retina The cancer is selected from blastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, throat cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. In some embodiments, the condition or disorder is a cancer selected from colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, and urothelial cancer, hi some embodiments, the condition or disorder is colorectal cancer.In some embodiments, the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. In some embodiments, the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. In some embodiments, the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. In some embodiments, the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the additional therapeutic agent is a statin. In some embodiments, the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. In some embodiments, the additional therapeutic agent is a survivin inhibitor. In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the additional therapeutic agent is a bone morphogenetic protein. In some embodiments, the budesonide and the additional therapeutic agent are administered simultaneously. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 hour to about 24 hours of each other. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 day to about 7 days of each other. In some embodiments, the budesonide and the additional therapeutic agent are formulated together in a pharmaceutical composition. In some embodiments, the budesonide and the additional therapeutic agent are administered every day, every second day, or every third day.In some embodiments, the method further comprises diagnosing an APC mutation in the subject.

[0010] In another aspect, the disclosure provides a method of treating familial adenomatous polyposis (FAP), comprising administering to a subject in need thereof a therapeutically effective amount of budesonide, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a therapeutically effective amount of an additional therapeutic agent, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the therapeutically effective amount of budesonide and the therapeutically effective amount of the additional therapeutic agent are synergistic. In some embodiments, the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. In some embodiments, the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. In some embodiments, the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. In some embodiments, the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the additional therapeutic agent is a statin. In some embodiments, the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. In some embodiments, the additional therapeutic agent is a survivin inhibitor. In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the additional therapeutic agent is a bone morphogenetic protein.In some embodiments, the budesonide and the additional therapeutic agent are administered simultaneously. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 hour to about 24 hours of each other. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 day to about 7 days of each other. In some embodiments, the budesonide and the additional therapeutic agent are formulated together in a pharmaceutical composition. In some embodiments, the budesonide and the additional therapeutic agent are administered daily, every 2 days, or every 3 days. In some embodiments, the subject has an APC mutation.

[0011] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; an additional therapeutic agent or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and a pharma- ceutically acceptable excipient.In some embodiments, the therapeutically effective amount of budesonide and the therapeutically effective amount of the additional therapeutic agent are synergistic.In some embodiments, the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. In some embodiments, the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. In some embodiments, the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. In some embodiments, the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or CTLA-4 receptor. In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the additional therapeutic agent is a statin. In some embodiments, the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. In some embodiments, the additional therapeutic agent is a survivin inhibitor. In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the additional therapeutic agent is a bone morphogenetic protein.

[0012] In another aspect, the disclosure provides a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof for use in the treatment of cancer.In another aspect, the disclosure provides a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a therapeutically effective amount of an additional therapeutic agent, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, for use in the treatment of cancer.In some embodiments, the therapeutically effective amount of budesonide and the therapeutically effective amount of the additional therapeutic agent are synergistic. In some embodiments, the cancer is acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer. Cancer, hemangioblastoma, hepatocellular carcinoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retina Selected from blastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, throat cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. In some embodiments, the cancer is selected from colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, and urothelial cancer, hi some embodiments, the cancer is colorectal cancer.In some embodiments, the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. In some embodiments, the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. In some embodiments, the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. In some embodiments, the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the additional therapeutic agent is a statin. In some embodiments, the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. In some embodiments, the additional therapeutic agent is a survivin inhibitor. In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the additional therapeutic agent is a bone morphogenetic protein. In some embodiments, the budesonide and the additional therapeutic agent are administered simultaneously. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 hour to about 24 hours of each other. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 day to about 7 days of each other. In some embodiments, the budesonide and the additional therapeutic agent are formulated together in a pharmaceutical composition. In some embodiments, the budesonide and the additional therapeutic agent are administered every day, every second day, or every third day.

[0013] In another aspect, the present disclosure provides a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug for use in treating a condition or disorder associated with an APC mutation.In another aspect, the present disclosure provides a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug, and a therapeutically effective amount of an additional therapeutic agent or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug for use in treating a condition or disorder associated with an APC mutation.In some embodiments, the therapeutically effective amount of budesonide and the therapeutically effective amount of the additional therapeutic agent are synergistic. In some embodiments, the condition or disorder is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, and gliomas. Neck cancer, hemangioblastoma, hepatocellular carcinoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retina The cancer is selected from blastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, throat cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. In some embodiments, the condition or disorder is a cancer selected from colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, and urothelial cancer.In some embodiments, the condition or disorder is colorectal cancer. In some embodiments, the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. In some embodiments, the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. In some embodiments, the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. In some embodiments, the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the additional therapeutic agent is a statin. In some embodiments, the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. In some embodiments, the additional therapeutic agent is a survivin inhibitor. In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the additional therapeutic agent is a bone morphogenetic protein. In some embodiments, the budesonide and the additional therapeutic agent are administered simultaneously. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 hour to about 24 hours of each other. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 day to about 7 days of each other. In some embodiments, the budesonide and the additional therapeutic agent are formulated together in a pharmaceutical composition.In some embodiments, the budesonide and additional therapeutic agent are administered every day, every second day, or every third day.

[0014] In another aspect, the disclosure provides a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof for use in the treatment of adenomatous polyposis coli (FAP). In another aspect, the disclosure provides a therapeutically effective amount of budesonide or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a therapeutically effective amount of an additional therapeutic agent or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof for use in the treatment of adenomatous polyposis coli (FAP). In some embodiments, the therapeutically effective amount of budesonide and the therapeutically effective amount of the additional therapeutic agent are synergistic. In some embodiments, the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. In some embodiments, the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. In some embodiments, the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. In some embodiments, the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the additional therapeutic agent is a statin. In some embodiments, the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. In some embodiments, the additional therapeutic agent is a survivin inhibitor.In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the additional therapeutic agent is a bone morphogenetic protein. In some embodiments, the budesonide and the additional therapeutic agent are administered simultaneously. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 hour to about 24 hours of each other. In some embodiments, the budesonide and the additional therapeutic agent are administered sequentially within about 1 day to about 7 days of each other. In some embodiments, the budesonide and the additional therapeutic agent are formulated together in a pharmaceutical composition. In some embodiments, the budesonide and the additional therapeutic agent are administered daily, every 2 days, or every 3 days. In some embodiments, the FAP is an APC mutated FAP.

[0015] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. A method of treating cancer, comprising administering a therapeutically effective amount of budesonide, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, to a subject in need thereof. (Item 2) The cancer is selected from the group consisting of acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, and liver cancer. Cell carcinoma, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland 2. The method of claim 1, wherein the cancer is selected from cancer, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovium, testicular cancer, small cell lung cancer, throat cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia, acute anaplastic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, and Waldenstrom's macroglobulinemia. (Item 3) 2. The method of claim 1, wherein the cancer is selected from colon cancer, gastric cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, and urothelial cancer. (Item 4) 2. The method of claim 1, wherein the cancer is colorectal cancer. (Item 5) 1. A method for treating familial adenomatous polyposis (FAP), comprising administering to a subject in need thereof a therapeutically effective amount of budesonide, or a pharma- ceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. (Item 6) 6. The method of any one of items 1 to 5, further comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof. (Item 7) 7. The method of item 6, wherein the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. (Item 8) 7. The method of claim 6, wherein the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. (Item 9) 7. The method of claim 6, wherein the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. (Item 10) The method of claim 6, wherein the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. (Item 11) 7. The method of claim 6, wherein the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. (Item 12) 7. The method of claim 6, wherein the additional therapeutic agent is napabucasin. (Item 13) 7. The method of claim 6, wherein the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon and antabuse. (Item 14) 7. The method of claim 6, wherein the additional therapeutic agent is a glucagon-like peptide. (Item 15) 7. The method of claim 6, wherein the additional therapeutic agent is a statin. (Item 16) 7. The method of claim 6, wherein the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. (Item 17) 7. The method of item 6, wherein the additional therapeutic agent is a survivin inhibitor. (Item 18) 7. The method of item 6, wherein the additional therapeutic agent is a TCF-4 inhibitor. (Item 19) 7. The method of claim 6, wherein the additional therapeutic agent is a bone morphogenetic protein. (Item 20) 20. The method of any one of items 6 to 19, wherein budesonide and the additional therapeutic agent are administered simultaneously. (Item 21) 20. The method of any one of items 6 to 19, wherein budesonide and the additional therapeutic agent are administered sequentially within about 1 hour to about 24 hours of each other. (Item 22) 20. The method of any one of items 6 to 19, wherein budesonide and the additional therapeutic agent are administered sequentially within about 1 day to about 7 days of each other. (Item 23) 21. The method of any one of items 6 to 20, wherein budesonide and the additional therapeutic agent are formulated together in a pharmaceutical composition. (Item 24) 24. The method of any one of items 6 to 23, wherein budesonide and the additional therapeutic agent are administered every day, every two days, or every three days. (Item 25) a therapeutically effective amount of budesonide, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof; an additional therapeutic agent, or a pharma- ceutically acceptable salt, solvate, hydrate, co-crystal, or prodrug thereof; and Pharmaceutically acceptable excipients 13. A pharmaceutical composition comprising: (Item 26) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is selected from 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, and tipiracil. (Item 27) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is selected from bevacizumab, ramucirumab, and aflibercept. (Item 28) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is selected from cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine. (Item 29) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is selected from regorafenib, sorafenib, and apatinib. (Item 30) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is a checkpoint inhibitor of the PD-1 receptor or the CTLA-4 receptor. (Item 31) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is napabucasin. (Item 32) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is selected from sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, and antabuse. (Item 33) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is a glucagon-like peptide. (Item 34) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is a statin. (Item 35) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is an all-trans retinoid or a 9-cis retinoid. (Item 36) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is a survivin inhibitor. (Item 37) 26. The pharmaceutical composition of item 25, wherein the additional therapeutic agent is a TCF-4 inhibitor. (Item 38) 26. The pharmaceutical composition of claim 25, wherein the additional therapeutic agent is a bone morphogenetic protein. [Brief description of the drawings]

[0016] [Figure 1] Figure 1 illustrates the reduction in the number of intestinal tumors in ApcMin / + mice fed a budesonide or sulindac-containing diet for 8 or 4 weeks (from 4 to 12 weeks of age, or from 8 to 12 weeks of age): the bar graph shows the % change in tumor number compared to untreated C57BL / 6 control mice. Each diet group had a total of 12 mice, 6 starting treatment at 4 weeks of age (before tumors developed) and 6 starting at 8 weeks of age (after tumors developed).

[0017] [Diagram 2] Figure 2 illustrates the change in size of intestinal tumors in ApcMin / + mice fed a budesonide or sulindac diet for 8 or 4 weeks (from 4 to 12 weeks of age, or from 8 to 12 weeks of age): the bar graph shows the % change in tumor size compared to untreated C57BL / 6 control mice. Tumor size was reduced when budesonide or sulindac was started before, but not after, adenoma development.

[0018] [Diagram 3]Figures 3A-3D illustrate that sulindac attenuates the expression of the anti-apoptotic protein survivin in human CRC cells; survivin and Bcl-2 expression were assessed in HT-29 cells treated with sulindac (200 μM). RNA and protein expression were measured by RT-PCR and Western blot, respectively. Figures 3A and 3B show ethidium bromide stained gels of survivin and Bcl-2 mRNA expression and graphs of quantified data. Figures 3C and 3D show Western blots and graphs of quantified data of survivin and Bcl-2 protein expression.

[0019] [Figure 4] Figures 4A-4D illustrate immunostaining using anti-5-methylcytidine antibody to assess global DNA methylation. Budesonide increases global DNA methylation of intestinal tissue in ApcMin / + mice. The signal intensity of immunostaining is decreased in the lower crypt region compared to the upper crypt and villus regions of the normal-appearing small intestine of B6 controls (Figure 4A) and ApcMin / + mice (Figure 4B). The signal intensity of immunostaining is decreased in adenomas of the small intestine of ApcMin / + mice (Figure 4C). Budesonide treatment induces an increase in both the proportion and intensity of adenoma cells staining positive for 5-methylcytidine (Figure 4D).

[0020] [Diagram 5]Figure 5 shows a circular ideogram of methylation levels, with hypermethylated genes (>2-fold increase compared to the mean) in red text and hypomethylated genes (>2-fold decrease) in green text, illustrating that budesonide increases DNA methylation in human CRC cells. Epigenetic profiling was performed on HT29 (APC mutant) cells in response to budesonide exposure, and DNA methylation profiling revealed that a global increase in methylation occurred across a large portion of the genome following budesonide exposure (69.3% of 1MB domains across the genome showed increased methylation in response to budesonide compared to controls, with statistically significant shifts in CpG methylation occurring at 235 unique CpG sites out of 1.9M analyzed). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present disclosure provides budesonide therapy for the treatment of cancer, particularly colorectal cancer or FAP.The present disclosure also provides combination therapy for the treatment of cancer, particularly colorectal cancer or FAP, for example, combination therapy of budesonide with other therapeutic agents, such as anti-cancer agents, for the treatment of cancer or FAP.Such combination provides synergistic effect in the treatment of cancer or FAP, particularly in the treatment of colorectal cancer. definition

[0022] General terms used herein preferably have the following meanings in the context of the present disclosure, unless otherwise indicated. Thus, definitions of general terms used in the context of the present invention are provided herein below.

[0023] The singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0024] The term "about" as used herein generally refers to an acceptable error range for a particular value as determined by one of ordinary skill in the art, which may depend in part on how the value is measured or determined. For example, "about" may mean within 1 or more than 1 standard deviation. Alternatively, "about" may mean within a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within 10-fold, within 5-fold, and within 2-fold of a value.

[0025] As used herein, the term "at least one" refers to one or more. For example, the term "at least one anti-cancer agent" means that the combination includes a single anti-cancer agent or more than one anti-cancer agent.

[0026] The term "effective amount" or "therapeutically effective amount" as used herein generally refers to an amount of a compound described herein that is sufficient to affect an intended, predetermined, or prescribed application, including, but not limited to, the treatment of a disease or condition. The therapeutically effective amount may vary depending on the application (e.g., in vitro or in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, and the mode of administration. The term may also apply to a dose that induces a particular response in a target cell, such as reduced proliferation or downregulation of the activity of a target protein. A particular dose may vary depending on the particular compound selected, the administration regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0027] As used herein, the term "pharmaceutically acceptable" means that the carrier, diluent, excipient, and / or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. "Pharmaceutically acceptable" also means that a composition or dosage form is, within the scope of sound medical judgment, suitable for use in animals or humans without causing undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0028] As used herein, the term "combination" or "pharmaceutical combination" refers to the combined administration of anti-cancer agents. The combinations of the present disclosure include, but are not limited to, budesonide, as well as 5-fluorouracil, albumin-bound paclitaxel, capecitabine, carboplatin, cisplatin, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, irinotecan liposomal, leucovorin (folinic acid), mitomycin, oxaliplatin, paclitaxel, trifluridine, tipiracil, bevacizumab, ramucirumab, aflibercept, cetuximab, panitumumab, erlotinib, trastuzumab, lapatinib, pertuzumab, trastuzumab emtansine, regorafenib, sorafenib, apatinib, At least one therapeutic agent comprises an anti-cancer agent selected from the following: PD-1 receptor or CTLA-4 receptor checkpoint inhibitor, napabucasin, sulindac, aspirin, celecoxib, difluoromethylornithine (DFMO), sodium butyrate, cyclosomatostatin, somatostatin, glucagon, antabuse, glucagon-like peptide, statin, all-trans retinoid (e.g., all-trans retinoic acid or ATRA), 9-cis retinoid (e.g., 9-cis retinoic acid), survivin inhibitor, TCF-4 inhibitor, or bone morphogenetic protein, and the therapeutic agent or anti-cancer agent can be administered to the subject in need thereof, for example, simultaneously or sequentially.Other anti-cancer agents are described herein or can be contemplated by those skilled in the art.

[0029] The terms "synergistic" or "synergistic effect" or "synergism" as used herein generally refer to an effect or effects of a combination of compositions that are greater than the effect or effects of each component alone, or that may be greater than the sum of the effect or effects of each component alone. A synergistic effect is greater than about 5% greater, greater than about 10% greater, greater than about 15% greater, greater than about 20% greater, greater than about 25% greater, greater than about 30% greater, greater than about 35% greater, greater than about 40% greater, greater than about 45% greater, greater than about 50% greater, greater than about 55% greater, greater than about 60% greater, greater than about 65% greater, greater than about 70% greater, greater than about 75% greater, greater than about 80% greater, greater than about 85% greater, greater than about 90% greater, greater than about 95 ... The effect may be greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 175%, greater than about 200%, greater than about 225%, greater than about 250%, greater than about 275%, greater than about 300%, greater than about 325%, greater than about 350%, greater than about 375%, greater than about 400%, greater than about 425%, greater than about 450%, greater than about 475%, or greater than 500% or more. The effect may be any of the measurable effects described herein. Advantageously, such synergistic effects between the drugs when combined may allow for the use of lower doses of one or both drugs, may provide greater efficacy at the same dose, and may prevent or delay the development of multi-drug resistance. As used herein, "synergistic amount" refers to such a dose. The combination index (CI) method of Chou and Talalay may be used to determine the synergistic, additive, or antagonistic effects of drugs used in combination. When the CI value is less than 1, there is synergy between the compounds used in the combination, when the CI value is equal to 1, there is an additive effect between the compounds used in the combination, and when the CI value is greater than 1, there is an antagonistic effect. Synergistic effects can be achieved by co-formulating the drugs of a pharmaceutical combination. Synergistic effects can be achieved by administering two or more drugs that are administered simultaneously or sequentially as separate formulations.

[0030] As used herein, the term "adenomatous polyposis coli gene" or "APC gene" or "APC" refers to a mammalian DNA sequence encoding the APC protein. An example of a human APC gene is located on chromosome 5 at 5q21-q22, GenBank: M74088.1. Synonyms of the human APC gene include BTPS2, DP2, DP2.5, DP3, PPP1R46, and "protein phosphatase 1, regulatory subunit 46". An example of a mouse APC gene is located on chromosome 18 at B1, MGI: 88039. Synonyms of the mouse APC gene include CC2, Min, mAPC, AI0147805, AU020952, and AW124434.

[0031] The term "adenomatous polyposis coli protein" or "APC protein" or "APC" as used herein refers to a mammalian protein sequence of 2843 amino acids. An example of a human APC sequence is GenBank: AAA03586. An example of a mouse APC sequence is GenBank: AAB59632.

[0032] The term "APC truncation" or "APC truncation mutant" or "APC truncation mutant" refers to a truncated protein product resulting from a mutation occurring within the APC gene. The APC truncation can be, for example, but not limited to, the 1309 amino acid product or the 1450 amino acid product.

[0033] The term "administering" as used herein includes administration in vivo as well as direct administration to tissue ex vivo.Generally, the composition can be administered systemically, either orally, bucally, parenterally, topically, by inhalation or insufflation (i.e. through the mouth or through the nose), or rectally, in a dosage unit formulation containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants, and vehicles as desired, or can be administered locally by means such as, but not limited to, injection, implantation, implantation, topical application, or parenterally.

[0034] As used herein, the terms "subject," "individual," and / or "patient" are used interchangeably and refer to members of any animal species of mammalian origin, including humans.

[0035] The term "inhibiting," as used herein, refers to reducing or modulating the chemical or biological activity of a substance or compound.

[0036] The terms "disease," "disorder," and / or "condition," as used herein, refer to a state of impaired health or abnormal functioning.

[0037] The term "drug" as used herein refers to a therapeutic agent or any substance used in the prevention, diagnosis, mitigation, treatment, or cure of disease.

[0038] The term "therapeutic agent" as used herein refers to a drug, molecule, nucleic acid, protein, metabolite, composition, or other substance that provides a therapeutic effect. The term "active" as used herein refers to an ingredient, component, or constituent of the described inventive composition that is responsible for the intended therapeutic effect. The terms "therapeutic agent" and "active agent" are used interchangeably herein.

[0039] The term "reduce" or "reducing," as used herein, refers to limiting the occurrence of a disorder in individuals at risk of developing the disorder.

[0040] As used herein, the terms "subject," or "individual," or "patient" are used interchangeably and refer to members of any animal species of mammalian origin, including humans.

[0041] The term "symptom" as used herein refers to a phenomenon that results from, accompanies, and serves as an indicator of a particular disease or disorder.

[0042] The term "therapeutic component" as used herein refers to a therapeutically effective dosage (i.e., dose and frequency of administration) that eliminates, reduces, or prevents the progression of a particular disease symptom in a certain percentage of the population.An example of a commonly used therapeutic component is ED50, which describes the dose in a particular dosage that is therapeutically effective for a particular disease symptom in 50% of the population.

[0043] The term "therapeutic effect" as used herein refers to an outcome of treatment whose results are deemed desirable and beneficial. Therapeutic effect may include, directly or indirectly, the arrest, reduction, or elimination of disease symptoms. Therapeutic effect may also include, directly or indirectly, the arrest, reduction, or elimination of the progression of disease symptoms.

[0044] As used herein, the term "mutation" refers to a change in the DNA sequence within an organism's genes or chromosomes, or a process by which such changes occur to chromosomes, either through an alteration in the nucleotide sequence of the DNA encoding the gene or through a change in the physical arrangement of the chromosome, creating a new characteristic or trait not found in the parental type. Three mechanisms of mutation include substitution (exchange of one base pair for another), addition (insertion of one or more bases into a sequence), and deletion (loss of one or more base pairs).

[0045] The terms "mutant" and "variant" are used interchangeably herein and refer to a nucleotide sequence that has substantial identity with a reference nucleotide sequence. Sequence differences can be the result of natural or designed changes in sequence or structure. Natural changes can occur in the nature of a particular nucleic acid sequence during normal reproduction or replication. Designed changes can be specifically designed and introduced into a sequence for a specific purpose. Such specific changes can be made in vitro using a variety of techniques.

[0046] The term "pharmaceutical composition" as used herein refers to a preparation containing a pharmaceutical agent, drug, metabolite, or active ingredient.

[0047] As used herein, the terms "treat," "treating," and / or "treatment" include abolishing, substantially inhibiting, slowing the progression of, or reversing a disease, disorder, or condition, substantially ameliorating the clinical symptoms of a disease, disorder, or condition, or substantially preventing the manifestation of clinical symptoms of a disease, disorder, or condition. Treating further refers to achieving one or more of: (a) reducing the severity of the disorder; (b) limiting the occurrence of symptoms characteristic of the disorder being treated; (c) limiting the worsening of symptoms characteristic of the disorder being treated; (d) limiting recurrence of the disorder in patients already with the disorder; (e) limiting the recurrence of symptoms in patients who were previously asymptomatic for the disorder; (f) reducing, alleviating, or ameliorating the symptoms of the disease or condition; (g) preventing additional symptoms, ameliorating or preventing the underlying cause of the symptoms; (h) inhibiting the disease or condition; (i) halting the occurrence of the disease or condition; (j) relieving the disease or condition; (k) causing regression of the disease or condition; (l) alleviating the symptoms caused by the disease or condition; and / or (m) halting the symptoms of the disease or condition, either prophylactically and / or therapeutically.

[0048] The term "condition" as used herein refers to a variety of health conditions and is meant to include disorders or diseases caused by underlying mechanisms or disorders in which truncated APC protein is expressed. A subject in need thereof is a patient who has or is at risk of having a disorder associated with an APC mutation.

[0049] As used herein, the terms "therapeutic amount" and / or "therapeutically effective amount" refer to an amount of a therapeutic agent necessary or sufficient to realize a desired biological effect. In combination with the teachings provided herein, by selecting among various therapeutic agents and weighting factors such as potency, relative bioavailability, patient weight, severity of adverse side effects and preferred mode of administration, an effective prophylactic or therapeutic treatment regimen can be designed that does not cause substantial toxicity and is still effective to treat a particular subject. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular described therapeutic agent, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the therapeutically effective amount of a particular described compound and / or other therapeutic agent without undue experimentation. In general, it is preferred to use the highest dose, i.e., the highest dose that is safe according to any medical judgment. The terms "dose" and "dosage" are used interchangeably herein. For any therapeutic agent described herein, the therapeutically effective amount can be initially determined from preliminary in vitro tests and / or animal models. Therapeutically effective amount can also be determined from human data.Applied dose can be adjusted based on the relative bioavailability and potency of administered compound.Adjusting dose to achieve maximum efficacy based on above and other methods is well known in the art and within the ability of the skilled artisan.Therapeutically effective amount can be currently approved recommended dosage and amount.

[0050] Detailed Description The present disclosure relates to the treatment of cancer, particularly colorectal cancer (CRC), and precancerous conditions such as familial adenomatous polyposis (FAP). Colorectal cancer and FAP are relatively common. CRC in particular is associated with high mortality. The present disclosure provides a method for treating CRC and FAP by using a combination therapy that includes at least budesonide.

[0051] Conventional treatment of adult patients with advanced cancer consists of combinations of cytotoxic chemotherapy agents (e.g., 5-FU-based regimens in the case of CRC), which are usually not curative and associated with significant toxicity. Some novel “targeted agents” developed against altered molecular pathways in cancer, although showing efficacy, do not produce the expected (>50%) tumor response rates and / or cure of cancer. Immunotherapeutic agents (i.e., immune checkpoint inhibitors) offer a promising approach by enhancing the body’s natural defenses to fight cancer. However, immunotherapy is primarily beneficial for only a small percentage (<10%) of all cancers, namely those with high mutation rates. In the case of CRC, only 3% of advanced stage tumors show a significantly elevated mutation rate (due to DNA mismatch repair or polymerase deficiency). Thus, only a small minority of patients would likely benefit from immunotherapy.

[0052] The majority of advanced CRCs (>80%) have inactivation of the tumor suppressor gene APC, and APC mutations are the main driver of tumor growth in most CRCs. APC, which does not act as a classical tumor suppressor, affects Wnt signaling, thereby regulating gene transcription. Wnts are a family of secreted cysteine-rich glycoproteins that have been implicated in regulating stem cell maintenance, proliferation, and differentiation during embryonic development. Typical Wnt signaling increases the stability of cytoplasmic 13-catenin by receptor-mediated inactivation of GSK-3 kinase activity, promoting translocation of 13-catenin to the nucleus. The typical Wnt signaling pathway also functions as a stem cell mitogen through stabilization of intracellular 13-catenin and activation of the 13-catenin / TCF / LEF transcription complex, leading to activation of the expression of cell cycle regulatory genes, such as Myc, cyclin Dl, EPhrinB (EPhB), and Msxl, which promote cell proliferation. APC is a negative regulator of Wnt signaling. Without this negative regulation, the Wnt pathway is more active and important in cancer.

[0053] The APC gene product is a 312 kDa protein consisting of multiple domains that bind to various proteins including beta-catenin, axin, C-terminal binding protein (CtBP), APC-stimulating guanine nucleotide exchange factor (Asef), Ras GTPase activating-like protein (IQGAP1), end binding-I (EB1), and microtubules. APC suppresses typical Wnt signaling, which is essential for tumorigenesis, development, and homeostasis of diverse cell types, including epithelial and lymphoid cells, but functions in several other fundamental cellular processes. These cellular processes include cell adhesion and migration, organization of actin and microtubule networks, spindle fiber formation, and chromosome segregation. Deregulation of these processes caused by mutations in APC has been implicated in the development and progression of colon cancer. The APC protein functions as a signaling depot or scaffold in that it physically interacts with several proteins associated with carcinogenesis. Loss of APC affects cell adhesion, cell migration, cytoskeleton, and chromosome segregation, and it is believed that APC mutations cause loss-of-function changes in colon cancer. Missense mutations result in point mutations in APC, while truncation mutations cause loss of large portions of the APC protein that contain defined regulatory domains.

[0054] Although the loss of function of APC may be partially accurate, a large proportion of colon cancer patients also have at least one truncated APC gene product, which is believed to have a gain of function. Thus, truncated APC proteins may play an active role in colon cancer development and progression, as opposed to recessive, for example, truncated APC can activate Asef and promote cell migration, whereas full-length APC does not. Defects in APC occur in a high proportion of colon cancer cases, but currently there are no therapeutics that target the vulnerabilities resulting from these defects.

[0055] While not wishing to be bound by any particular theory, it is believed that most advanced CRCs (>80%) have inactivation of the tumor suppressor gene APC. Similarly, while not wishing to be bound by any particular theory, several lines of evidence are believed to indicate that APC mutations drive the development and growth of CRC: (i) APC mutations result in constitutively active WNT signaling via downstream activation of TCF4, inducing transcription of genes that drive cell proliferation, and WNT signaling is altered in approximately 95% of human CRCs, primarily due to biallelic mutations in the APC gene; (ii) APC mutations are sufficient for early CRC development; familial adenomatous polyposis (FAP) patients with germline APC mutations have a 100% risk of developing CRC if left untreated; (iii) tumors arising from APC mutations are more predictive than tumors arising from DNA mismatch repair mutations. (iv) the severity of any given APC mutation (without wishing to be bound by any particular theory, most often thought to result in cleavage and inactivation of the APC protein) correlates with the severity of CRC; (v) the characteristics of the second hit of APC depend on the nature of the first hit of APC; (vi) APC mutations are required for the maintenance of colon cancer; (vii) transfection of APC into CRC cells induces cell cycle arrest and apoptosis; (viii) restoration of wild-type Apc in CRC leads to cell differentiation and re-establishes crypt homeostasis; (ix) APC mutations that drive CRC growth have been shown to do so by causing an overpopulation of SCs.

[0056] The present disclosure provides a method for screening drugs that target APCs. Min Provides the use of a mouse. Apc Min The only mutation that the mice have is the germline Apc mutation, Apc Min Mice consequently develop multiple intestinal tumors. Budesonide, a steroidal anti-inflammatory drug that is active against lung cancer development, was tested as a treatment for CRC and showed no significant effect on Apc MinThey found that budesonide strongly reduced (88%) the incidence of intestinal tumors induced by the mutation. The effect of budesonide was comparable to that of the nonsteroidal anti-inflammatory drug (NSAID) sulindac (90% reduction).

[0057] As described herein, Apc Min The mice can be used to screen drugs for their ability to target mechanisms disrupted by APC mutations. The only mutation these mice have is the germline Apc mutation, which by itself is sufficient to cause the mice to develop multiple intestinal tumors. Min mice carry a single tumor-initiating mutation (Apc Min ), whereas an acquired second Apc mutation leads to complete Apc inactivation and tumor development. Thus, any effect by a drug that inhibits the tumorigenic process is the result of the drug's ability to modify the neoplastic tissue and counteract the APC-based mechanisms that drive tumor growth. Without wishing to be bound by any particular theory, a strategy for discovering new drugs for aggressive colon tumors (human CRC) is to use Apc Min This is likely due to the evaluation of agents that inhibit tumor development in mice, because: 1) one class of agents known to prevent CRC is also active against metastatic CRC; i.e., NSAIDs (e.g., sulindac, celecoxib, aspirin) inhibit Apc Min 1) prevention of tumor and human CRC, and metastatic CRC patients taking NSAIDs had a significantly increased survival; 2) APC mutations occur early in CRC development, so that all tumor cells harbor them during CRC development (including cancer stem cells), and APC mutations are the primary driver of tumor growth in most CRCs.

[0058] The present disclosure provides for identifying drugs that act against various APC mutations. MinThe use of the model has been applied as an innovative approach to identify drugs active against CRC, which may have various APC mutations. In one embodiment, this approach is used to identify budesonide as a CRC candidate drug as described herein. Without wishing to be bound by any particular theory, Apc Min Although the mice carry a germline Apc mutation that predisposes to tumors, the intestinal tumors that arise and grow spontaneously in vivo are believed to be due to further inactivation of Apc (a second hit).Similarly, without wishing to be bound by any particular theory, this model is believed to be useful because any drug that has activity against multiple APC mutations will be effective against many of the processes and pathways that are impaired by different APC mutations.

[0059] The wild-type APC gene typically encodes a large scaffold-type protein with seven major functional domains that interact with and regulate at least 22 different proteins and their associated pathways (WNT is just one of these pathways). Thus, depending on the location of any given APC mutation, this may affect different cellular processes that differentially promote tumor development. In the development of GI tumors in vivo in Min mice, the acquired (somatic) mutations that inactivate the second allele of Apc are diverse and many may be scattered throughout the genetic sequence of Apc. Thus, each different tumor that develops may theoretically have a different second hit in Apc. Thus, the diverse Apc genotypes of multiple intestinal tumors in Min mice provide a model that mimics the situation in human CRC, whereby the APC mutations in different human CRCs are diverse and widely distributed throughout the APC sequence. Given that the nature (type and location) of APC mutations may vary from tumor to tumor in individual cancer patients, it is important to identify drugs that are effective against any of the alterations in APC that can impair the function of the many cellular pathways that APC controls, as well as the effect of these alterations on the tissue dynamics that drive cancer growth. Thus, without wishing to be bound by any particular theory, it is believed that the approach described herein differs from approaches that develop agents that simply target components in one pathway (e.g., WNT signaling) or use drug screens that require only one specific mutation in APC. Without wishing to be bound by any particular theory, budesonide is believed to be effective against APC Min Being effective in inhibiting the development and growth of most intestinal tumors in mice, budesonide is likely to be effective against tumors with different APC genotypes in CRC patients.

[0060] Without wishing to be bound by any particular theory, the present disclosure is based at least in part on the fact that budesonide preferentially inhibits the growth of malignant human colon cells with adenomatous polyposis coli (APC) mutation.In some embodiments, this effect is enhanced when budesonide is combined with nonsteroidal anti-inflammatory drugs (NSAIDs).Similarly, without wishing to be bound by any particular theory, it is believed that budesonide and NSAIDs are both anti-inflammatory drugs, but they act through different molecular mechanisms.

[0061] In some embodiments, budesonide inhibits the growth of various human CRC cell lines. In one embodiment, cells with mutant APC are twice (or more) sensitive to growth inhibition by budesonide than wild-type APC cells. Increased differentiation and apoptosis occur in parallel with growth inhibition. In some embodiments, NSAIDs, such as sulindac or aspirin, enhance the antitumor activity of budesonide. In some embodiments, budesonide and NSAIDs have synergistic effects.

[0062] The present disclosure provides for selecting drug combinations that are synergistic. Without wishing to be bound by any particular theory, to create new drug combinations that are synergistic, the selection of drugs includes: i) Apc MinIt is believed that the antitumor activity in the model may be based on ii) their mechanism of action. The mechanism of action of a drug may affect the efficacy when administered in combination. For example, when two drugs act through the same or similar mechanism, they often show additive activity when combined. It is believed that additive activity is equal to the sum of the effects of the two drugs given separately. In contrast, and without wishing to be bound by any particular theory, it is believed that when two drugs act through different mechanisms, the combination of drugs can produce synergistic activity. That is, the effect of the two drugs administered together is greater than the sum of their separate effects at the same dose. In order to identify drugs that may have synergistic activity against advanced CRC when administered in combination, different drugs that act through different mechanisms were selected. In one embodiment, two anti-inflammatory drugs were selected that not only have strong activity against tumor development in ApcMin mice, but also have different molecular mechanisms of action. Thus, since budesonide and NSAID have different mechanisms of action, it is believed that they have synergistic activity when administered in combination.

[0063] As described herein, the present disclosure provides a combination therapy comprising budesonide and one or more additional therapeutic agents.In some embodiments, the combination therapy is for the treatment of various cancers, including but not limited to colorectal cancer.In some embodiments, the combination therapy is for the treatment of FAP.In some embodiments, the combination therapy is for the treatment of any condition in subjects with PC mutation.As used herein, combination therapy includes both the method and composition of the treatment comprising one or more therapeutic agents. In one embodiment, the therapeutic agent is budesonide: [ka]

[0064] In some embodiments, budesonide is administered rectally (PR). In some embodiments, budesonide is administered as one dose (2 mg) PR twice daily for two weeks, followed by one dose PR once daily in the evening for four weeks.

[0065] In some embodiments, budesonide is administered orally (PO). In some embodiments, budesonide is administered as a capsule, e.g., an enteric coated and / or time-release capsule. In some embodiments, budesonide is administered as a 3 mg tablet, e.g., an enteric coated and / or time-release tablet. In some embodiments, budesonide is administered as a 9 mg dose. In some embodiments, budesonide is administered orally at a 9 mg dose every morning for up to 8 weeks. In some embodiments, budesonide is administered orally at a 9 mg dose every morning for up to 8 weeks, and the 8 week course may be repeated. In some embodiments, budesonide is administered orally at a 6 mg dose every morning. In some embodiments, budesonide is administered orally at a 6 mg dose every morning for up to 3 months.

[0066] In some embodiments, budesonide can be administered by inhalation. In some embodiments, budesonide is administered as an aerosol, for example, at a dose of (80mcg / 4.5mcg) / actuation, or at a dose of (160mcg / 4.5mcg) / actuation. In some embodiments, budesonide is administered as an aerosol at a dose of 160mcg / 9mcg (2 actuations of 80mcg / 4.5mcg) every 12 hours, or at a dose of 320mcg / 9mcg (2 actuations of 160mcg / 4.5mcg) every 12 hours. In some embodiments, budesonide is administered as an aerosol at a dose of 160mcg / 9mcg (2 actuations of 80mcg / 4.5mcg) every 12 hours, or at a dose of 320mcg / 9mcg every 12 hours. In some embodiments, budesonide is administered as an aerosol at a dose of 160 mcg / 4.5 mcg.

[0067] In some embodiments, budesonide can be administered intranasally. In some embodiments, budesonide is administered intranasally at a dose of 32 mcg / actuation. In some embodiments, budesonide is administered intranasally at a dose of 1 spray per nostril once a day (64 mcg / day) or at a dose of 4 sprays per nostril once a day (256 mcg / day). In some embodiments, budesonide is administered intranasally at a dose of 2 sprays per nostril once a day (128 mcg / day).

[0068] In some embodiments, the additional therapeutic agent is 5-fluorouracil. In some embodiments, 5-fluorouracil (5-FU) is administered at a dose of 500 mg / m 2 or 450-600 mg / m 2 or 200-400 mg / m 2 It is given by continuous intravenous infusion once daily at a dose of

[0069] In some embodiments, the additional therapeutic agent is albumin-bound paclitaxel. In some embodiments, the albumin-bound paclitaxel is at 125 mg / m 2 is administered intravenously over 30-40 minutes on days 1, 8, and 15 of each 28 day cycle at a dose of 260 mg / m 2 is administered intravenously over 30 minutes every 3 weeks at a dose of 100 mg / m 2 will be administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of each 21-day cycle.

[0070] In some embodiments, the additional therapeutic agent is capecitabine. In some embodiments, capecitabine is administered at 1250 mg / m 2 is administered twice daily every 21 days for 2 weeks at a dose of 1000-1250 mg / m 2 is administered orally twice daily on days 1-14 of every 21 days.

[0071] In some embodiments, the additional therapeutic agent is carboplatin. In some embodiments, carboplatin is administered at 360 mg / m 2 It is given intravenously at a dose of 10 mg once every 4 weeks.

[0072] In some embodiments, the additional therapeutic agent is cisplatin. In some embodiments, cisplatin is administered at a dose of 50-100 mg / m 2 In some embodiments, cisplatin is administered intravenously at a dose of 20 mg / m 2 / day for 5 days / cycle. In some embodiments, cisplatin is administered intravenously at a dose of 50-70 mg / m 2 In some embodiments, cisplatin is administered intravenously at a dose of 50 mg / m in cycles every 3-4 weeks. In some embodiments, cisplatin is administered at a dose that corresponds to previous radiation or chemotherapy. In some embodiments, cisplatin is administered at a dose of 50 mg / m 2 / cycle. In some embodiments, cisplatin is administered in doses that are repeated every 4 weeks. In some embodiments, cisplatin is administered in doses of 75-100 mg / m 2 In some embodiments, cisplatin is administered intravenously at a dose of 90 to 270 mg / m 2 In some embodiments, cisplatin is administered intraperitoneally at a dose of 75-100 mg / m. In some embodiments, cisplatin is administered at a dose that is repeated every 3 weeks. In some embodiments, cisplatin is administered at a dose of 75-100 mg / m. 2 In some embodiments, cisplatin is administered intravenously at a dose of 100 mg / m 2 It is given intravenously at a dose of 10 mg once every 4 weeks.

[0073] In some embodiments, the additional therapeutic agent is dacarbazine. In some embodiments, dacarbazine is administered intravenously at a dose of 2-4.5 mg / kg once daily for 10 days. In some embodiments, dacarbazine is administered as a repeat dose every 4 weeks. In some embodiments, dacarbazine is administered at a dose of 250 mg / m 2In some embodiments, dacarbazine is administered intravenously at a dose of 150 mg / m once daily for five days. In some embodiments, dacarbazine is administered as a repeat dose every three weeks. In some embodiments, dacarbazine is administered at a dose of 150 mg / m 2 once daily for five days, repeated every four weeks. In some embodiments, dacarbazine is administered intravenously at a dose of 375 mg / m 2 is given intravenously on day 1 and repeated every 15 days.

[0074] In some embodiments, the additional therapeutic agent is docetaxel. In some embodiments, docetaxel is administered at a dose of 75-100 mg / m 2 on day 1. In some embodiments, docetaxel is administered every 21 days.

[0075] In some embodiments, the additional therapeutic agent is doxorubicin. In some embodiments, doxorubicin is administered at a dose of 60-75 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of 60 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of 40-60 mg / m 2 In some embodiments, doxorubicin is administered intravenously at a dose of 20 mg / m 2 / dose is administered weekly.

[0076] In some embodiments, the additional therapeutic agent is epirubicin. In some embodiments, epirubicin is at 90 mg / m 2 is given intravenously on day 1, every 3 weeks.

[0077] In some embodiments, the additional therapeutic agent is etoposide. In some embodiments, etoposide is administered at a dose of 50-100 mg / m 2 / day on days 1-5. In some embodiments, etoposide is administered intravenously at a dose of 100 mg / m 2 / day is given intravenously on days 1, 3, and 5.

[0078] In some embodiments, the additional therapeutic agent is gemcitabine. In some embodiments, gemcitabine is administered at a dose of 1000 mg / m 2 is administered intravenously over 30 minutes once a week for seven weeks at a dose of 1000 mg / m 2 It is administered intravenously once weekly for three weeks of each 28-day cycle at a dose of

[0079] In some embodiments, the additional therapeutic agent is ifosfamide. In some embodiments, ifosfamide is administered at a dose of 1.2 g / m 2 Administered intravenously over 30 minutes on days 1-5 of each 3-4 week period at a dose of 100 mg / day.

[0080] In some embodiments, the additional therapeutic agent is irinotecan. In some embodiments, irinotecan is administered at 250-350 mg / m on day 1 of every 21 days. 2 In some embodiments, irinotecan is administered intravenously at a dose of 150-180 mg / m 2 on day 1 of every 14 days. In some embodiments, irinotecan is administered intravenously at a dose of 125 mg / m 2 is given intravenously on days 1 and 8 of every 21 days.

[0081] In some embodiments, the additional therapeutic agent is irinotecan liposomal. In some embodiments, irinotecan liposomal is at 70 mg / m 2 is given as an intravenous infusion over 90 minutes every 2 weeks.

[0082] In some embodiments, the additional therapeutic agent is leucovorin (folinic acid). In some embodiments, the leucovorin is at 400 mg / m 2 is given intravenously on day 1 at a dose of

[0083] In some embodiments, the additional therapeutic agent is mitomycin. In some embodiments, mitomycin is at 20 mg / m 2In some embodiments, mitomycin is administered intravenously at a dose of 10 mg / m 2 is given as an intravenous bolus on days 1-29 at a dose not to exceed 20 mg / dose.

[0084] In some embodiments, the additional therapeutic agent is oxaliplatin. In some embodiments, the oxaliplatin is at 85 mg / m 2 It is administered intravenously at a dose of

[0085] In some embodiments, the additional therapeutic agent is paclitaxel. In some embodiments, paclitaxel is administered at a dose of 135-250 mg / m 2 on day 1 of every 21 days. In some embodiments, paclitaxel is administered intravenously at a dose of 80 mg / m2 on day 1 of every week of every 28 days.

[0086] In some embodiments, the additional therapeutic agent is trifluridine. In some embodiments, the additional therapeutic agent is trifluridine and tipiracil. In some embodiments, trifluridine and tipiracil are administered at 35 mg / m 2 is administered orally twice daily on days 1-5 and 8-12 of each 28-day cycle.

[0087] In some embodiments, the additional therapeutic agent is napabucasin. In some embodiments, napabucasin is administered orally as two daily doses of 240 mg.

[0088] In some embodiments, the additional therapeutic agent is bevacizumab, hi some embodiments, bevacizumab is administered intravenously at a dose of 5-10 mg / kg every two weeks.

[0089] In some embodiments, the additional therapeutic agent is ramucirumab. In some embodiments, ramucirumab is administered at a dose of 8 mg / kg as an intravenous infusion over 1 hour every 2 weeks.

[0090] In some embodiments, the additional therapeutic agent is aflibercept. In some embodiments, aflibercept is administered at a dose of 4 mg / kg by intravenous infusion over 1 hour every 2 weeks.

[0091] In some embodiments, the additional therapeutic agent is cetuximab. In some embodiments, cetuximab is administered at 400 mg / m 2 is given intravenously over 2 hours at a dose of 250 mg / m 2 It is given as a 60-minute intravenous infusion once weekly at a dose of

[0092] In some embodiments, the additional therapeutic agent is panitumumab, which is administered at a dose of 6 mg / kg as an intravenous infusion over 60 minutes (90 minutes if the dose is >1 g) every 14 days.

[0093] In some embodiments, the additional therapeutic agent is erlotinib. In some embodiments, the erlotinib is administered orally at a dose of 100-150 mg / day.

[0094] In some embodiments, the additional therapeutic agent is trastuzumab. In some embodiments, trastuzumab is administered intravenously at a loading dose of 8 mg / kg on day 1 of cycle 1, followed by 6 mg / kg intravenously every 21 days with chemotherapy, or at a loading dose of 6 mg / kg on day 1 of cycle 1, followed by 4 mg / kg intravenously every 14 days with chemotherapy.

[0095] In some embodiments, the additional therapeutic agent is lapatinib. In some embodiments, lapatinib is administered orally once daily on days 1-21 at a dose of 1250-1500 mg.

[0096] In some embodiments, the additional therapeutic agent is pertuzumab, which is administered at a dose of 840 mg administered intravenously over 60 minutes, followed by 420 mg administered intravenously over 30-60 minutes every three weeks.

[0097] In some embodiments, the additional therapeutic agent is trastuzumab emtansine. In some embodiments, trastuzumab emtansine is administered by intravenous infusion at a dose of 3.6 mg / kg every 3 weeks.

[0098] In some embodiments, the additional therapeutic agent is regorafenib. In some embodiments, regorafenib is administered orally once daily at a dose of 160 mg (four 40 mg tablets) for the first 21 days of each 28-day cycle.

[0099] In some embodiments, the additional therapeutic agent is sorafenib. In some embodiments, sorafenib is administered orally at a dose of 400 mg every 12 hours.

[0100] In some embodiments, the additional therapeutic agent is apatinib mesylate. In some embodiments, the apatinib mesylate is administered orally at a dose of 500 mg once daily every four weeks.

[0101] In some embodiments, the additional therapeutic agent is a PD-1 receptor checkpoint inhibitor. In some embodiments, the additional therapeutic agent is a CTLA-4 checkpoint inhibitor. In some embodiments, the additional therapeutic agent is nivolumab. In some embodiments, nivolumab is administered intravenously over 30 minutes at a dose of 240 mg every two weeks. In some embodiments, the additional therapeutic agent is pembrolizumab. In some embodiments, pembrolizumab is administered intravenously at a dose of 200 mg every three weeks.

[0102] In some embodiments, the additional therapeutic agent is sulindac, hi some embodiments, the sulindac is administered orally at a dose of 150-200 mg every 12 hours.

[0103] In some embodiments, the additional therapeutic agent is aspirin, hi some embodiments, the aspirin is administered orally at a dose of 100-300 mg every 12 hours.

[0104] In some embodiments, the additional therapeutic agent is celecoxib. In some embodiments, celecoxib is administered at a 100 mg dose of Celebrex administered twice daily, or at a 400 mg dose of Celebrex administered twice daily.

[0105] In some embodiments, the additional therapeutic agent is tretinoin. In some embodiments, tretinoin is at 45 mg / m 2 The dose is given orally in divided doses every 12 hours.

[0106] In some embodiments, the additional therapeutic agent is DFMO. In some embodiments, the DFMO is administered at a dose of 500 mg once daily.

[0107] In some embodiments, the additional therapeutic agent is sodium butyrate. In some embodiments, the sodium butyrate is administered at a dose that is evaluated in a Phase I trial.

[0108] In some embodiments, the additional therapeutic agent is a survivin inhibitor. In some embodiments, the survivin inhibitor is administered at a dose evaluated in a Phase I trial. In some embodiments, the additional therapeutic agent is AICAR. In some embodiments, the additional therapeutic agent is arctigenin. In some embodiments, the additional therapeutic agent is cephalochromine. In some embodiments, the additional therapeutic agent is FL118. In some embodiments, the additional therapeutic agent is flavopiridol. In some embodiments, the additional therapeutic agent is ICG-001. In some embodiments, the additional therapeutic agent is KPT-185. In some embodiments, the additional therapeutic agent is lapatinib. In some embodiments, the additional therapeutic agent is MK-2206. In some embodiments, the additional therapeutic agent is NU6140. In some embodiments, the additional therapeutic agent is panepoxidone. In some embodiments, the additional therapeutic agent is piperine. In some embodiments, the additional therapeutic agent is purvalanol A. In some embodiments, the additional therapeutic agent is Shepherdin. In some embodiments, the additional therapeutic agent is terameprocol. In some embodiments, the additional therapeutic agent is UC112. In some embodiments, the additional therapeutic agent is YM155.

[0109] In some embodiments, the additional therapeutic agent is cortistatin. In some embodiments, the cortistatin is administered at a dose that is evaluated in a Phase I trial.

[0110] In some embodiments, the additional therapeutic agent is cyclosomatostatin. In some embodiments, the cyclosomatostatin is administered at a dose that is evaluated in a Phase I trial.

[0111] In some embodiments, the additional therapeutic agent is Sandostatin. In some embodiments, Sandostatin LAR (octreotide) is administered subcutaneously in a dose of 100-600 mcg / day in divided doses every 6-12 hours.

[0112] In some embodiments, the additional therapeutic agent is glucagon. In some embodiments, glucagon is administered intramuscularly / subcutaneously / intravenously at a dose of 0.2-1 mg (1 unit).

[0113] In some embodiments, the additional therapeutic agent is a glucagon-like peptide. In some embodiments, the glucagon-like peptide is administered at a dose evaluated in a Phase I trial. In some embodiments, the additional therapeutic agent is somatostatin. In some embodiments, the additional therapeutic agent is a glucagon analog. In some embodiments, the additional therapeutic agent is cortistatin. In some embodiments, the additional therapeutic agent is cyclosomatostatin. In some embodiments, the additional therapeutic agent is Sandostatin LAR (octreotide). In some embodiments, the additional therapeutic agent is glucagon.

[0114] In some embodiments, the additional therapeutic agent is Antabuse, hi some embodiments, Antabuse is administered orally once daily at a dose of 125-500 mg.

[0115] In some embodiments, the additional therapeutic agent is a TCF-4 inhibitor. In some embodiments, the TCF-4 inhibitor is administered at a dose evaluated in a Phase I trial. In some embodiments, the additional therapeutic agent is an anti-RPL29 antibody. In some embodiments, the additional therapeutic agent is BHQ880. In some embodiments, the additional therapeutic agent is CGP04909. In some embodiments, the additional therapeutic agent is CWP232291. In some embodiments, the additional therapeutic agent is DKN-01. In some embodiments, the additional therapeutic agent is G007-LK. In some embodiments, the additional therapeutic agent is G244-LM. In some embodiments, the additional therapeutic agent is ICG-001. In some embodiments, the additional therapeutic agent is IWR-1. In some embodiments, the additional therapeutic agent is JW55. In some embodiments, the additional therapeutic agent is LGK974. In some embodiments, the additional therapeutic agent is OMP-18R5. In some embodiments, the additional therapeutic agent is OMP-54F28. In some embodiments, the additional therapeutic agent is PKF115-584. In some embodiments, the additional therapeutic agent is PRI-724. In some embodiments, the additional therapeutic agent is Rp-8-Br-cAMPS. In some embodiments, the additional therapeutic agent is XAV939.

[0116] In some embodiments, the additional therapeutic agent is bone morphogenetic protein.In some embodiments, the bone morphogenetic protein is administered at a dose that is evaluated in phase I study.In some embodiments, the additional therapeutic agent is bone morphogenetic protein selected from BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP11 and BMP15.

[0117] In some embodiments, the additional therapeutic agent is atorvastatin, hi some embodiments, the atorvastatin is administered orally once daily at a dose of 10-80 mg.

[0118] In some embodiments, the additional therapeutic agent is fluvastatin, hi some embodiments, the fluvastatin is administered orally once daily at a dose of 20-80 mg.

[0119] In some embodiments, the additional therapeutic agent is lovastatin, hi some embodiments, lovastatin is administered orally once daily at a dose of 10-80 mg.

[0120] In some embodiments, the additional therapeutic agent is pravastatin, hi some embodiments, the pravastatin is administered orally once daily at a dose of 10-80 mg.

[0121] In some embodiments, the additional therapeutic agent is rosuvastatin, hi some embodiments, the rosuvastatin is administered orally once daily at a dose of 5-40 mg.

[0122] In some embodiments, the additional therapeutic agent is simvastatin, hi some embodiments, the simvastatin is administered orally once daily at a dose of 5-40 mg.

[0123] In some embodiments, the additional therapeutic agent is pitavastatin, hi some embodiments, pitavastatin is administered orally once daily at a dose of 2-4 mg.

[0124] The present disclosure provides pharmaceutically acceptable salts of any therapeutic agent and / or compound described herein.Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts.The acid that is added to a compound to form an acid addition salt can be an organic acid or an inorganic acid.The base that is added to a compound to form a base addition salt can be an organic base or an inorganic base.In some examples, the pharmaceutically acceptable salt is a metal salt.In some examples, the pharmaceutically acceptable salt is an ammonium salt.

[0125] Acid addition salts may result from the addition of an acid to a compound described herein. In some examples, the acid is an organic acid. In some examples, the acid is an inorganic acid. Non-limiting examples of suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, nicotinic acid, isonicotinic acid, lactic acid, salicylic acid, 4-aminosalicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, and the like. acid), saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, oxalic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, glycolic acid, malic acid, cinnamic acid, mandelic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, phenylacetic acid, N-cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2-phosphoglyceric acid, 3-phosphoglyceric acid, glucose-6-phosphate, and amino acids.

[0126] Metal salts can be generated from the addition of inorganic bases to the compounds of the present invention. Inorganic bases consist of a metal cation paired with a basic counterion, such as hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0127] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0128] Ammonium salts can be generated by the addition of ammonia or organic amine to the compounds described herein.Non-limiting examples of suitable organic amines include triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, pyrazine, piperazine, ethylenediamine, N,N'-dibenzylethylenediamine, procaine, chloroprocaine, choline, dicyclohexylamine and N-methylglucamine.

[0129] Non-limiting examples of suitable ammonium salts include triethylamine salts, diisopropylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, morpholine salts, N-methylmorpholine salts, piperidine salts, N-methylpiperidine salts, N-ethylpiperidine salts, dibenzylamine salts, piperazine salts, pyridine salts, pyrazole salts, imidazole salts, pyrazine salts, piperazine salts, ethylenediamine salts, N,N'-dibenzylethylenediamine salts, procaine salts, chloroprocaine salts, choline salts, dicyclohexylamine salts, and N-methylglucamine salts.

[0130] Non-limiting examples of suitable acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, carbonate, bicarbonate, nicotinate, isonicotinate, lactate, salicylate, 4-aminosalicylate, tartrate, ascorbate, gentisate, gluconate, glucuronate, and the like. salt), saccharate, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, citrate, oxalate, maleate, hydroxymaleate, methylmaleate, glycolate, malate, cinnamate, mandelate, 2-phenoxybenzoate, 2-acetoxybenzoate, embonate, phenylacetate, N-cyclohexylsulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, ethane-1,2-disulfonate, 4-methylbenzenesulfonate, naphthalene-2-sulfonate, naphthalene-1,5-disulfonate, 2-phosphoglycerate, 3-phosphoglycerate, glucose-6-phosphate, and amino acid salts.

[0131] The compounds and therapeutic agents described herein may, in some instances, exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds and therapeutic agents presented herein include all diastereomeric, enantiomeric, and epimeric forms and the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography, or by formation of diastereomers and separation by recrystallization, or by chromatography, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 2001, incorporated herein by reference for this disclosure). 1981). Stereoisomers can also be obtained by stereoselective synthesis.

[0132] The compounds and therapeutic agents described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds and therapeutic agents described herein may be in the form of pharmaceutically acceptable salts. Similarly, the active metabolites of these compounds and therapeutic agents with the same type of activity are included within the scope of this disclosure. In addition, the compounds and therapeutic agents described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, etc. The solvated forms of the compounds and therapeutic agents presented herein are also considered to be disclosed herein.

[0133] The compounds and therapeutic agents described herein include compounds and therapeutic agents that exhibit their natural isotopic abundance, as well as compounds and therapeutic agents in which one or more of the atoms have been artificially enriched in a particular isotope having the same atomic number, but with an atomic mass or mass number different from that found predominantly in nature. All isotopic variations of the compounds and therapeutic agents of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. For example, hydrogen is: 1 H (protium), 2 H (deuterium), and 3 It has three naturally occurring isotopes called H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium may confer certain therapeutic advantages, such as increasing in vivo half-life and / or exposure, or provide compounds useful for investigating in vivo pathways of drug excretion and metabolism. Isotopically enriched compounds may be prepared.

[0134] Compounds and therapeutic agents described herein having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in Z or E form (or cis or trans form), if applicable. In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z, E and tautomeric forms as well.

[0135] In certain cases, the compounds and therapeutic agents described herein may be prodrugs, for example, carboxylic acids present in the parent compound are present as esters. The term "prodrug" is intended to encompass compounds that are converted to the disclosed agent, i.e., parent compound, under physiological conditions. One way to create a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In certain embodiments, the prodrug is converted by the enzyme activity of the host animal, for example, the enzyme activity in a specific target cell in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present disclosure.

[0136] Prodrugs are often useful because in some circumstances they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent compound is not. Prodrugs may serve to enhance the cell permeability of the compound compared to the parent drug. For example, a prodrug may have improved cell permeability compared to the parent compound. A prodrug may also have improved solubility in pharmaceutical formulations compared to the parent drug. In some embodiments, the design of a prodrug increases the lipophilicity of the drug. In some embodiments, the design of a prodrug increases the effective water solubility.

[0137] The present disclosure provides a method for preventing or reducing the recurrence of cancer in a subject in need thereof. The present disclosure also provides a method for preventing or reducing the recurrence of FAP in a subject in need thereof. The present disclosure also provides a method for preventing or reducing the recurrence of a disease or disorder associated with an APC mutation in a subject in need thereof. In certain embodiments, the term "prevent" or "preventing" in relation to a disease or disorder may refer to a compound or combination that reduces the occurrence of a disorder or condition in a treated sample compared to an untreated control sample in a statistical sample, or delays the occurrence or reduces the severity of one or more symptoms of a disorder or condition compared to an untreated control sample. The method includes administering the combination therapy described herein to treat minimal residual disease and / or as a maintenance therapy, for example, as a continuous or extended therapy after the cessation of another cancer treatment. For example, the combination therapy may be administered after the cessation of another treatment, for example, chemotherapy, radiation therapy, and / or surgery.

[0138] In some aspects, the combinations described herein, such as the combinations of budesonide and additional therapeutic agents described herein, can be utilized for the treatment of cancer, including but not limited to colorectal cancer. The combination treatments described herein can reduce the likelihood of metastasis in a subject in need thereof. In some embodiments, the metastasis is a solid tumor. In some embodiments, the metastasis is a liquid tumor. The cancer that is a liquid tumor can be, for example, a cancer that occurs in the blood, bone marrow, and lymph nodes, and can include, for example, leukemia, myeloid leukemia, lymphocytic leukemia, lymphoma, Hodgkin's lymphoma, melanoma, and multiple myeloma. Leukemias include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and hairy cell leukemia. Examples of solid tumor cancers include prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi's sarcoma, skin cancer, skin squamous cell carcinoma, kidney cancer, head and neck cancer, throat cancer, squamous cell carcinoma that forms on the moist mucosal lining of the nose, mouth, and throat, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, and kidney cancer. In some embodiments, the condition treated by the methods described herein is a melanoma cell, a prostate cancer cell, a testicular cancer cell, a breast cancer cell, a brain cancer cell, a pancreatic cancer cell, a colon cancer cell, a thyroid cancer cell, a stomach cancer cell, a lung cancer cell, an ovarian cancer cell, a Kaposi's sarcoma cell, a skin cancer cell, a kidney cancer cell, a head and neck cancer cell, a throat cancer cell, a squamous cell carcinoma cell, a bladder cancer cell, an osteosarcoma cell, a cervical cancer cell, an endometrial cancer cell, an esophageal cancer cell, a liver cancer cell, or a kidney cancer metastasis.

[0139] The methods described herein can also be used to inhibit the progression of metastatic cancer tumors.Non-limiting examples of cancer include adrenocortical carcinoma, pediatric adrenocortical carcinoma, AIDS-related cancer, anal cancer, appendix cancer, basal cell carcinoma, pediatric basal cell carcinoma, bladder cancer, pediatric bladder cancer, bone cancer, brain tumor, pediatric astrocytoma, pediatric brain stem glioma, pediatric central nervous system atypical teratoid / rhabdoid tumor, pediatric central nervous system embryonal tumor, pediatric central nervous system embryonal tumor, pediatric craniopharyngioma brain tumor, pediatric ependymoma brain tumor, breast cancer, pediatric bronchial tumor, carcinoid tumor, pediatric carcinoid tumor, gastrointestinal carcinoma oid tumor, cancer of unknown primary site, childhood cancer of unknown primary site, childhood cardiac tumor, cervical cancer, childhood cervical cancer, childhood chordoma, chronic myeloproliferative disorder, colon cancer, colorectal cancer, childhood colorectal cancer, extrahepatic bile duct cancer, ductal carcinoma in situ (DCIS), endometrial cancer, esophageal cancer, childhood esophageal cancer, childhood esthesioneuroblastoma, eye cancer, malignant fibrous histiocytoma of bone, gallbladder cancer, gastric (stomach) cancer, childhood gastric cancer, gastrointestinal stromal tumor (GIST), childhood gastrointestinal stromal Tumor (GIST), childhood extracranial germ cell tumor, extragonadal germ cell tumor, gestational trophoblastic tumor, glioma, head and neck cancer, childhood head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, kidney cancer, renal cell kidney cancer, Wilms tumor, childhood kidney tumor, Langerhans cell histiocytosis, laryngeal cancer, childhood laryngeal cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia, lip cancer , liver cancer (primary), childhood liver cancer (primary), lobular carcinoma in situ (LCIS), lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, AIDS-related lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma (CNS), melanoma, childhood melanoma, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, childhood malignant mesothelioma, metastatic squamous cell carcinoma of the neck with unknown primary site, midline tract carcinoma with NUT genecarcinoma), oral cancer, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndrome, myelodysplastic tumor, myeloproliferative neoplasm, multiple myeloma, nasal cavity cancer, nasopharyngeal cancer, pediatric nasopharyngeal cancer, neuroblastoma, oral cavity cancer, pediatric oral cancer, oropharyngeal cancer, ovarian cancer, pediatric ovarian cancer, epithelial ovarian cancer, low malignant potential ovarian cancer, pancreatic cancer, pediatric pancreatic cancer, pediatric neuroendocrine tumor (islet cell tumor), pediatric papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell tumor, pediatric pleuropulmonary blastoma, prostate cancer of the rectum, transitional cell carcinoma of the renal pelvis, retinoblastoma, salivary gland cancer, childhood salivary gland cancer, Ewing family of tumors, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, childhood rhabdomyosarcoma, soft tissue sarcoma, uterine sarcoma, Sézary syndrome, childhood skin cancer, non-melanoma skin cancer, small intestine cancer, squamous cell carcinoma, childhood squamous cell carcinoma, testicular cancer, childhood testicular cancer, throat cancer, thymoma and thymic carcinoma, childhood thymoma and thymic carcinoma, thyroid cancer, childhood thyroid cancer, transitional cell carcinoma of the urinary tract, urethral cancer, endometrial cancer, vaginal cancer, vulvar cancer, and Waldenstrom's macroglobulinemia.

[0140] The combination therapy described herein can be used with other therapies, such as radiation therapy. The chemotherapy and radiation therapy treatment regimen can include a finite number of cycles of on-drug therapy followed by off-drug therapy, or can include a finite time frame for administering chemotherapy or radiation therapy. The protocol can be determined by clinical trials, drug labels, and clinical personnel along with the subject being treated. The number of cycles of chemotherapy or radiation therapy or the total length of the chemotherapy or radiation therapy regimen can vary depending on the subject's response to cancer treatment. The agents described herein can be administered after the chemotherapy or radiation therapy treatment regimen is completed.

[0141] In some aspects, the combinations described herein can be utilized to treat subjects in need thereof.In some examples, the subjects treated by the methods and compositions disclosed herein can be human subjects.The subjects treated by the methods and compositions disclosed herein can be non-human animals.Non-limiting examples of non-human animals can include non-human primates, livestock animals, pets, and laboratory animals.

[0142] In certain embodiments, the combination therapy described herein can be administered as separate agents or can be combined into a single pharmaceutical composition.For example, the combination of budesonide and an additional therapeutic agent described herein can be formulated as two separate pharmaceutical compositions or can be formulated together into a single pharmaceutical composition.

[0143] In certain embodiments, the present disclosure provides pharmaceutical compositions comprising budesonide or a salt thereof, e.g., for oral or parenteral administration. In some aspects, the pharmaceutical compositions comprise budesonide or a salt thereof in an amount of at least about 1 mg to about 1000 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 400 mg, or about 250 mg to about 350 mg. For example, the pharmaceutical composition of the present disclosure may contain about 100mg, about 120mg, about 140mg, about 160mg, about 180mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 380mg, about 400mg, about 420mg, about 440mg, about 460mg, about 480mg, or about 500mg of budesonide or its salt.For compounds described herein, such as budesonide formulated in pharmaceutical compositions in the form of a salt, the amount of compound may reflect the weight of the free base, and not the weight of the salt form.In certain embodiments, the pharmaceutical composition of budesonide or its salt does not contain an additional anti-cancer agent.In certain embodiments, the pharmaceutical composition includes an additional anti-cancer agent described herein.

[0144] The therapeutically effective amount of budesonide or its salt can be expressed as mg of compound per kg of body mass of a subject. In some examples, the therapeutically effective amount can be at least about 0.1 mg / kg to about 20 mg / kg, such as about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, or about 20 mg / kg. For compounds described herein, such as budesonide, that are formulated into pharmaceutical compositions in the form of a salt, the therapeutically effective amount of the compound can reflect the weight of the free base, and not the weight of the salt form.

[0145] In certain embodiments, the disclosure provides a pharmaceutical composition for oral or parenteral administration comprising, for example, budesonide or a salt thereof, The pharmaceutical composition may comprise at least about 1 mg to about 1000 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 200 mg to about 800 mg, or about 300 mg to about 8000 mg of budesonide or a salt thereof. For example, the pharmaceutical compositions of the present disclosure may comprise about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1020 mg, about 1040 mg, about 1050 The dosage form may contain about 0 mg, about 580 mg, about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 760 mg, about 780 mg, about 800 mg, about 820 mg, about 840 mg, about 860 mg, about 880 mg, about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, or about 1000 mg of budesonide or a salt thereof.

[0146] In certain embodiments, the present disclosure provides a pharmaceutical composition for oral or parenteral administration, for example, comprising budesonide or a salt thereof. The pharmaceutical composition may comprise at least about 0.5 mg to about 50 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, or about 1 mg to about 5 mg of budesonide or a salt thereof. For example, the pharmaceutical composition of the present disclosure may comprise about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of budesonide or a salt thereof.

[0147] In certain embodiments, the formulations of the present disclosure comprise budesonide or a salt thereof, wherein the budesonide or salt thereof is about 70% to about 99.99%, about 80% to about 99.9%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, about 97% to about 99%, about 98% to about 99%, about 98% to about 99.9%, about 99% to about 99.99%, about 99.5% to about 99.99%, about 99.6% to about 99.99%, about 99.8 to about 99.99%, or about 99.9% to about 99.99% free of impurities.

[0148] In certain embodiments, pharmaceutical compositions of the present disclosure include pharmaceutical compositions having amounts of both budesonide or a salt thereof and an additional therapeutic agent, such as amounts described herein, e.g., 100-400 mg of budesonide or a salt thereof and 200-800 mg of an additional therapeutic agent. In certain embodiments, pharmaceutical compositions of the present disclosure include pharmaceutical compositions having both budesonide or a salt thereof and an additional therapeutic agent, e.g., 100-400 mg of budesonide or a salt thereof, and 1-10 mg of an additional therapeutic agent.

[0149] The pharmaceutical compositions disclosed herein may be in the form of liquid formulations, solid formulations, or combinations thereof. Non-limiting examples of formulations may include tablets, capsules, pills, gels, pastes, liquid solutions, and creams. In some cases, budesonide or its salts may be in a crystallized form. In pharmaceutical compositions that include two or more therapeutic agents, each agent may be crystallized separately and then combined, or they may be crystallized together. The composition may include two or more therapeutic agents in one or more physical states. For example, the composition may be a tablet that includes one therapeutic agent in a solid formulation and another therapeutic agent or drug in a gel formulation. In certain embodiments, the composition is a single pharmaceutical composition that includes budesonide or its salts in a first physical state and an additional therapeutic agent in a second physical state.

[0150] The composition of the present disclosure may further comprise excipient or additive.Excipient may comprise any and all solvents, coatings, chelating agents, flavoring agents, coloring agents, lubricants, disintegrants, preservatives, sweeteners, antifoaming agents, buffering agents, polymers, antioxidants, binders, diluents, and vehicles (e.g., carriers).Generally, excipients are compatible with the therapeutic composition of the present disclosure.

[0151] The liquid preparation for oral administration may take the form of, for example, solution, syrup or suspension, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use.Such liquid preparations can be prepared by conventional methods with pharmaceutically acceptable additives, such as suspending agents (for example, sorbitol syrup, methylcellulose or edible hydrogenated fat), emulsifying agents (for example, lecithin or acacia), non-aqueous vehicles (for example, almond oil, oily esters or ethyl alcohol), preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid), and artificial or natural coloring agents and / or sweeteners.

[0152] The present disclosure further encompasses anhydrous compositions and dosage forms that contain active ingredients, since water can accelerate the decomposition of some compounds. The anhydrous compositions and dosage forms of the present disclosure can be prepared using anhydrous or low moisture content ingredients and low moisture or low humidity conditions. The compositions and dosage forms of the present disclosure that contain lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacture, packaging, and / or storage. Anhydrous compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, anhydrous compositions can be packaged using materials that prevent exposure to water so that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, airtight foils, plastics, unit dose containers, blister packs, and strip packs.

[0153] The components described herein can be combined in intimate mixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. Carriers can take a wide variety of forms depending on the form of preparation desired for administration. When preparing compositions for oral dosage forms, any of the conventional pharmaceutical media can be used as carriers, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. for oral liquid preparations (e.g., suspensions, solutions, and elixirs) or aerosols; or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents for oral solid preparations, and in some embodiments, lactose is not used. For example, suitable carriers include powders, capsules, and tablets with solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0154] Some examples of materials that can serve as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0155] Binders suitable for use in the dosage form include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0156] Examples of suitable fillers for use in the compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0157] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein can be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, as well as various sweeteners or flavoring agents, coloring materials or dyes, and, if necessary, emulsifying and / or suspending agents.

[0158] In one embodiment, the composition may contain a solubilizer to ensure good solubilization and / or dissolution of the disclosed compound and to minimize precipitation of the disclosed compound.This may be particularly important for compositions for parenteral use, such as injection compositions.Solubilizers such as surfactants may also be added to increase the solubility of hydrophilic drugs and / or other components, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0159] The pharmaceutical compositions described herein may be suitable for oral administration to subjects in need thereof.In some cases, sustained release formulations for oral administration may be prepared to achieve controlled release of active agent upon contact with body fluids in the digestive tract and provide a substantially constant and effective level of active agent in plasma.Crystalline forms may be embedded for this purpose in a polymer matrix of biodegradable polymers, water-soluble polymers, or a mixture of both, and optionally a suitable surfactant.Embedding in this context may mean incorporating microparticles into a polymer matrix.Controlled release formulations may also be obtained through encapsulation of dispersed microparticles or emulsified microdroplets via known dispersion or emulsion coating techniques.

[0160] In some embodiments, the composition can be formulated into a food composition. For example, the composition can be a beverage or other liquid, solid food, semi-solid food, with or without a food carrier. For example, the composition can include black tea supplemented with any of the compositions described herein. The composition can be a dairy product supplemented with any of the compositions described herein. In some embodiments, the composition can be formulated in a food composition. For example, the composition can include a beverage, solid food, semi-solid food, or food carrier.

[0161] In certain embodiments, pharmaceutical preparations may be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulation agents such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical preparations for parenteral administration include, for example, aqueous solutions of the active compound in water-soluble form. Suspensions of the active compound can be prepared, for example, as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, isopropyl palmitate, or medium-chain triglycerides, or liposomes. In a preferred embodiment, the formulation for parenteral administration is an aqueous suspension.

[0162] The therapeutic agents described herein may be present in the composition within a range of concentrations, the range being defined by upper and lower values ​​selected from any of the concentrations previously described. For example, the therapeutic agents of the present disclosure may be present in the formulation at a concentration of about 1 nM to about 100 mM, about 10 nM to about 10 mM, about 100 nM to about 1 mM, about 500 nM to about 1 mM, about 1 mM to about 50 mM, about 10 mM to about 40 mM, about 20 mM to about 35 mM, or about 20 mM to about 30 mM.

[0163] The method of preparing a composition comprising a therapeutic agent as described herein may include formulating the therapeutic agent with one or more inert pharma-ceutically acceptable excipients.Liquid compositions include, for example, a solution in which one or more therapeutic agents are dissolved, an emulsion containing one or more therapeutic agents, or a solution containing liposomes, micelles, or nanoparticles containing one or more therapeutic agents as disclosed herein.These compositions may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharma-ceutically acceptable additives.

[0164] Injectable preparations may be presented in unit dosage form, for example in ampoules or multi-dose containers with the addition of preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be provided in unit dosage or multi-dose containers, for example in sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, for example saline or sterile pyrogen-free water, immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type previously described.

[0165] Pharmaceutical preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injections of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or liposomes.

[0166] The compositions described herein, such as pharmaceutical compositions of budesonide or its salts or co-formulations of budesonide or its salts with additional therapeutic agents, can be administered once or more than once a day. The compositions can be administered sequentially (e.g., taken every day without any break in the duration of the treatment regimen). In some examples, the treatment regimen can be for less than one week, one week, two weeks, three weeks, one month, or longer than one month. In some examples, the compositions of the present disclosure are administered for a period of at least 12 weeks. In other examples, the compositions are administered for one day, at least two consecutive days, at least three consecutive days, at least four consecutive days, at least five consecutive days, at least six consecutive days, at least seven consecutive days, at least eight consecutive days, at least nine consecutive days, at least ten consecutive days, or longer than at least ten consecutive days. In some examples, the therapeutically effective amount can be administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, eight times a week, nine times a week, ten times a week, eleven times a week, twelve times a week, thirteen times a week, fourteen times a week, fifteen times a week, sixteen times a week, seventeen times a week, eighteen times a week, nineteen times a week, twenty times a week, twenty-five times a week, thirty-five times a day, thirty-five times a day, forty times a day, or more than forty times a day. In some examples, the composition is administered at least twice a day. In further examples, the composition is administered at least every hour, at least every 2 hours, at least every 3 hours, at least every 4 hours, at least every 5 hours, at least every 6 hours, at least every 7 hours, at least every 8 hours, at least every 9 hours, at least every 10 hours, at least every 11 hours, at least every 12 hours, at least every 13 hours, at least every 14 hours, at least every 15 hours, at least every 16 hours, at least every 17 hours, at least every 18 hours, at least every 19 hours, at least every 20 hours, at least every 21 hours, at least every 22 hours, at least every 23 hours, or at least every day.

[0167] The pharmaceutical composition of the present disclosure can be administered either acutely or chronically. The pharmaceutical composition of the present invention can be administered as a single treatment or a course of treatment. Treatment can be administered once a day, twice a day, three times a day, in the morning, in the evening, before bedtime, or continuously throughout the day. Treatment can be applied daily, every other day, every third day, twice a week, once a week, once every two weeks, monthly, every six weeks, every two months, every three months, every six months, once a year, once every two years, once every five years, or as needed.

[0168] In certain embodiments, the dose of the administered drug may be temporarily reduced or temporarily suspended for a period of time. In certain embodiments, the patient has a drug holiday during which no drug is administered or a reduced amount of drug is administered for a period of time. The drug holiday may be, for example, between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or a period longer than 28 days. The drug holiday may be about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months. Dose reductions during drug holidays can be, for example, 10%-100% of the original administered dose, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. By way of further example, dose reductions can be between 10%-100%, between 20%-80%, between 30%-70%, between 50%-90%, between 80%-100%, or between 90%-100%.

[0169] After improvement of the patient's condition has occurred, a maintenance dose can be administered as necessary. The dosage or frequency of administration, or both, can then be reduced as a function of symptoms to a level that can maintain the improved disease, disorder, or condition.

[0170] Additional methods of administering the combinations and formulations described herein include, for example, but are not limited to, delivery via intestinal routes, including oral, gastric, or duodenal feeding tube, rectal suppositories, rectal enemas, parenteral routes, injections, infusions, intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, intracameral, epidural, subcutaneous, inhalation, transdermal, transmucosal, sublingual, buccal, topical, epicutaneous, skin, enema, ear drops, intranasal, and vaginal administration.The therapeutic agents described herein can be administered locally to the area requiring treatment, for example, by local injection during surgery, topical application such as cream or ointment, injection, catheter, or implant.Administration can also be performed by direct injection into the site of diseased tissue or organ.

[0171] The length of administration period and / or dosage can be determined by a physician or any other type of clinician.The physician or clinician can observe the response of the subject to the administered composition and adjust the dosage based on the subject's performance.For example, the dosage of the subject who shows a reduced effect in energy regulation can be increased to achieve the desired result.

[0172] In some embodiments, the combination therapies described herein can be administered together at the same time by the same route, or can be administered separately. In some embodiments, the components in the composition can be administered using the same or different routes of administration.

[0173] In some embodiments, the present disclosure also provides a method for producing the compositions described herein. In some embodiments, producing the compositions described herein includes mixing or combining two or more components.

[0174] In some embodiments, the composition can be combined or mixed with a pharmacoactive or therapeutic agent, a carrier, and / or an excipient. Examples of such components are described herein. The combined composition can be formed into a unit dosage as a tablet, capsule, gel capsule, sustained release tablet, etc.

[0175] In some embodiments, the compositions are prepared so as to achieve a solid composition containing a substantially homogeneous mixture of one or more components, such that the one or more components are uniformly dispersed throughout the composition, thereby allowing the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0176] The unit doses can be packaged in a container that is delivered to the user. The unit doses can be packaged in a tube, jar, box, vial, bag, tray, drum, bottle, syringe, or can.

[0177] Another aspect of the present disclosure provides that after the combination composition described herein is administered for a specified period, the desired effect is achieved in one or more subjects.For example, the beneficial effect of the composition described herein can be observed after the composition is administered to the subject for 1, 2, 3, 4, 6, 8, 10, 12, 24 or 52 weeks.

[0178] In certain embodiments, the combination therapy described herein can be administered by combination treatment regimen.The combination treatment regimen can include treatment regimen in which the administration of the compound described herein or its pharmaceutically acceptable salt is started before, during, or after the treatment with the second agent described herein, and continues until any time during or after the end of the treatment with the second agent.The present disclosure also includes treatment in which the compound described herein or its pharmaceutically acceptable salt and the second agent used in combination are administered at the same time or at different times, and / or at shorter or longer intervals during the treatment period.The combination treatment further includes cyclical treatment that starts and stops at different times to help with the clinical management of the patient.

[0179] In certain embodiments, combination therapy can provide therapeutic benefits due to the difference in toxicity associated with the two treatment modalities.For example, treatment with budesonide can bring about certain toxicity that is not observed with additional therapeutic agents, and vice versa.This difference in toxicity therefore allows each treatment to be administered at a dose where said toxicity is absent or minimal, so that combination therapy provides therapeutic doses while avoiding the toxicity of each of the components of the combined drug together.Furthermore, if the therapeutic effect achieved as a result of combination treatment is synergistic, the dose of each of the drugs can be reduced even further, thus reducing the associated toxicity to an even greater extent.

[0180] The therapeutic agent described herein or its pharma- ceutically acceptable salts as well as combination therapy may be administered before, during, or after the onset of a disease or condition, and the timing of administration of the therapeutic agent, combination thereof, or composition containing the therapeutic agent may vary. The therapeutic agent described herein may be used as a prophylactic agent and may be administered continuously to a subject with a tendency to develop a condition or disease to prevent the onset of the disease or condition. The compounds and compositions thereof described herein may be administered to a subject during or as soon as possible after the onset of symptoms. The therapeutic agent described herein may be administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the period necessary for the treatment of the disease. EXAMPLES

[0181] The following examples are presented for the purpose of illustrating various embodiments of the present invention, and are not meant to limit the present invention in any manner. These examples, together with the methods described herein, are representative of currently preferred embodiments, are exemplary, and are not intended as limitations on the scope of the present invention. Modifications thereof and other uses encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.

[0182] Example 1: Budesonide prevents the development of intestinal tumors caused by Apc mutations Budesonide is a steroidal anti-inflammatory drug that is active against lung cancer development and was tested as a drug for CRC. Budesonide was administered to mice with Apc, a mouse model of hereditary CRC (FAP) in humans. Min / + This was evaluated in mice, which, like FAP patients, harbor a germline Apc mutation and spontaneously develop multiple intestinal tumors. Min This was compared to sulindac, a "standard of care" NSAID drug known to inhibit tumor development in mice. Min / +Mice and control mice (C57BL6) were fed a budesonide or sulindac-containing diet starting at 4 or 8 weeks of age (corresponding to the ages before and after intestinal tumors developed, respectively). At 12 weeks, mice were sacrificed and the intestine was analyzed for adenomas. Budesonide reduced the number of tumors by 88% (P=0.009) when started before intestinal adenomas were established and by 60% (p=0.03) when started after adenomas developed (Figure 1). Min / + Figure 2 illustrates the reduction in intestinal tumor numbers in mice fed budesonide or sulindac-containing diets for 8 or 4 weeks (from 4 to 12 weeks of age, or from 8 to 12 weeks of age); bar graphs show the % change in tumor numbers compared to untreated C57BL / 6 control mice; each diet group had 12 mice total, 6 started treatment at 4 weeks of age (before tumors appeared) and 6 started at 8 weeks of age (after tumors appeared). Tumor size was reduced when budesonide was started before adenoma appearance, but not when started after (Figure 2 shows the results of a comparison of Apc mice fed budesonide or sulindac-containing diets for 8 or 4 weeks (from 4 to 12 weeks of age, or from 8 to 12 weeks of age). Min / + (A) illustrates the change in intestinal tumor size in mice; the bar graph shows the % change in tumor size compared to untreated C57BL / 6 control mice; tumor size was reduced when budesonide or sulindac was started before, but not after, the development of adenomas. The antitumor response of budesonide was comparable to that induced by the NSAID sulindac administered before and after the development of intestinal tumors (90% reduction and 90% reduction, respectively; FIG. 1). Without wishing to be bound by any particular theory, it is concluded that budesonide has potent activity against the development of multiple tumors (a combination of inherited first hit and acquired second hit) that would otherwise be induced by various Apc mutations, and also against the regression of many tumors after they had already developed.

[0183] Example 2: Mechanism of Action - Sulindac Without wishing to be bound by any particular theory, sulindac may induce adenoma regression in FAP patients by several possible mechanisms, and may inhibit Apc Min Sulindac is thought to inhibit adenoma formation in the lining of the blood. One molecular mechanism appears to involve the ability of sulindac, via its sulfonated metabolites, to inhibit both COX-1 and COX-2 enzymatic activity, thereby inhibiting prostaglandin synthesis. However, the effects of another metabolite, the sulfone product, appear to be COX-independent.

[0184] Another mechanism contributing to the antitumor effect of sulindac is its ability to induce apoptosis and reduce cell proliferation. This mechanism appears to involve a COX-independent mechanism in which sulindac (and other NSAIDs) induces degradation of beta-catenin, inactivation of Tcf-4, decreased expression of an antiapoptotic protein (survivin; Figure 3) and increased apoptosis in human CRC cells. Figures 3A-3D illustrate that sulindac attenuates the expression of the antiapoptotic protein survivin in human CRC cells. To this end, the expression of survivin and Bcl-2 was evaluated in HT-29 cells treated with sulindac (200 μM). RNA and protein expression were measured by RT-PCR and Western blot, respectively. Figures 3A and 3B show ethidium bromide stained gels and graphs of quantification data for mRNA expression of survivin and Bcl-2. Figures 3C and 3D show graphs of Western blot and quantification data for protein expression of survivin and Bcl-2; sulindac induces a monotonic decrease in survivin but not Bcl-2 expression in HT-29 cells. This also shows that sulindac induces apoptosis by decreasing the expression of survivin (a WNT target gene) in HT29 CRC cells.

[0185] Example 3: Mechanism of Action - Budesonide Without wishing to be bound by any particular theory, budesonide is believed to have a different mechanism of action than NSAIDs, including, but not limited to, increased DNA methylation in adenoma (Figure 4) and human CRC cells (Figure 5), which is consistent with reports that budesonide induces remethylation of lung DNA in association with its ability to prevent lung tumors in animal models. Min / + As shown in Fig. 4 for intestinal tumors from mice, adenomas appear to be hypomethylated (Fig. 4), which is consistent with previous reports that DNA hypomethylation is a hallmark of many tumors, including CRC. Min / + This is consistent with molecular studies in which mice were crossed with mice carrying a germline mutation in the DNA methyltransferase (Dnmtl) gene that results in a decrease in global DNA methylation. Such crossed mice showed increased incidence of adenomas, tumors that also show loss of the remaining wild-type Apc allele through loss of heterozygosity. In treated mice, budesonide was found to increase both the signal intensity and the proportion of adenoma cells staining positive for DNA methylation (Figure 4). Thus, our finding that budesonide increases DNA methylation in adenomas corroborates the finding that budesonide induces DNA remethylation in lung cancer and, without wishing to be bound by any particular theory, suggests one possible explanation for why budesonide inhibits intestinal tumor development.

[0186] Figures 4A-4D illustrate immunostaining using an anti-5-methylcytidine antibody to assess global DNA methylation; budesonide inhibits Apc Min / + Increases global DNA methylation in intestinal tissue in Apc mice. The signal intensity of immunostaining was significantly higher in the lower crypt region than in B6 control mice (Figure 4A) and Apc mice (Figure 4B). Min / + The signal intensity of the immunostaining was reduced compared to the upper crypt and villus regions of the normal-appearing small intestine of mice (Figure 4B). Min / +In mouse small intestinal adenomas, the signal intensity is decreased (Figure 4C). Budesonide treatment induces an increase in both the proportion and intensity of 5-methylcytidine staining positive adenoma cells (Figure 4D). Budesonide increased both the signal intensity (1.9-fold) and the proportion of 5-methylcytidine staining positive cells in these adenomas.

[0187] FIG. 5 shows that budesonide increases DNA methylation in human CRC cells. To determine whether budesonide increases DNA methylation in human CRC cells, epigenetic profiling was performed on HT29 (APC mutant) cells in response to budesonide exposure. DNA methylation profiling revealed that after budesonide exposure, a global increase in methylation occurred across most of the genome. Indeed, 69.3 percent of 1MB domains across the genome showed increased methylation in response to budesonide compared to controls (FIG. 5). A statistically significant shift in CpG methylation occurred at 235 unique CpG sites (out of 1.9M analyzed). The figure shows a circular schematic of methylation abundance, with hypermethylated genes (>2-fold increase compared to the mean) in red text and hypomethylated genes (>2-fold decrease) in green text.

[0188] Example 4: Budesonide preferentially inhibits the growth of malignant human colon cells harboring APC mutations. Without wishing to be bound by any particular theory, it appears that budesonide preferentially inhibits the growth of malignant human colon cells that have APC mutations. Also, without wishing to be bound by any particular theory, it appears that this effect is enhanced when budesonide is combined with additional therapeutic agents, including, for example, but not limited to, NSAIDs. The effect of various therapeutic agents on CRC cells with mutant or wild-type APC is analyzed in vitro. The ability of budesonide to inhibit the in vitro growth of various human CRC cell lines has been confirmed. Budesonide selectively inhibits the growth of cells with mutant APC compared to cells with wild-type APC. Budesonide inhibits the growth of APC cells with germline mutations in the Apc tumor suppressor protein.Min Inhibits intestinal tumor initiation and growth in mice. Similarly, APC inactivation is a driver of human CRC growth. Without wishing to be bound by any particular theory, Apc Min Drugs that inhibit intestinal tumor development in mice are likely to be candidate inhibitors of human CRC growth.

[0189] The antitumor activity of budesonide against human CRC cells harboring mutant and wild-type APC is evaluated. Five CRC cell lines harboring homozygous mutant APC (SW480, HT29, COLO320, CaCo2, DiFi) and two CRC cell lines harboring wild-type APC (LoVo and HCT116) are evaluated. The antitumor effect of budesonide is evaluated by cell growth assays (counting cell numbers over time, immunostaining for MCM2 and Ki67, MTT assay and BrdU incorporation). Secondary outcome measures include: differentiation markers (CK20 = pan-differentiation; lectin = Paneth cells; chromogranin A = enteroendocrine cells; intestinal alkaline phosphatase = absorptive cells; Muc2 = goblet cells), and apoptosis (survivin and annexin V). Response to the drug is determined by dose-response and time-course experiments. In time course experiments, treated cells are sampled at 4 and 8 h and then at 12-h intervals up to 48 h. In dose response experiments, budesonide is added in a dose range of 1-25 μM. All experiments are repeated at least three times on different days and in different cultures. Without wishing to be bound by any particular theory, the acceptance criteria are believed to be the following: cells with mutant APC are twice as (or more) sensitive to growth inhibition by budesonide than wild-type APC cells. Increased differentiation and apoptosis occur in parallel with growth inhibition.

[0190] Without wishing to be bound by any particular theory, it is believed that budesonide preferentially inhibits the growth of CRC cells with mutant APC compared to cells with wild-type APC. Similarly, without wishing to be bound by any particular theory, it is believed that cells with mutant APC are more sensitive to the growth inhibitory effect of budesonide compared to wild-type APC cells. In some embodiments, the increase in sensitivity is two-fold or greater. Without wishing to be bound by any particular theory, it is believed that budesonide selectively targets APC mutant CRC cells. In some embodiments, both mutant APC and wild-type APC CRC cells are growth inhibited (in some embodiments, >50).

[0191] Example 5: NSAIDs Sulindac or Aspirin Enhance the Antitumor Activity of Budesonide Without wishing to be bound by any particular theory, it is believed that budesonide, when combined with other therapeutic agents, such as but not limited to NSAIDs, has synergistic anti-CRC effect.Similarly, without wishing to be bound by any particular theory, budesonide and sulindac both inhibit the development and growth of tumors in Min mice, and act through different mechanisms, so it is believed that budesonide acts synergistically with sulindac or other NSAIDs against CRC cells.When combined with another therapeutic agent, such as but not limited to NSAIDs such as sulindac or aspirin, budesonide increases the anti-CRC effect compared to when either drug is administered alone. Dose-response analysis of sulindac (1-200 μM) and aspirin (0.1-10 mM) is performed on five CRC cell lines with homozygous mutant APC (SW480, HT29, COLO320, CaCo2, DiFi) and two CRC cell lines with wild-type APC (LoVo and HCT116). Combinations of additional therapeutic agents, such as but not limited to NSAIDs and budesonide at the EC20 dose, are tested for synergistic activity. Higher doses (e.g., EC50 doses) or different treatment or time schedules are attempted as well. For statistical analysis, data are expressed as mean ± SEM (n=3). Student's t-tests are used to compare results between control and treated samples; when more than two groups are analyzed, ANOVA is used. While not wishing to be bound by any particular theory, it is believed that the acceptance criterion is that budesonide and NSAIDs have a synergistic effect.

[0192] Without wishing to be bound by any particular theory, it is believed that the effect of budesonide and an additional therapeutic agent, such as but not limited to sulindac, when administered together is greater than the sum of their separate effects, consistent with a synergistic effect. In some embodiments, the effect of the combined agents is equal to the sum of the effects of budesonide and an additional therapeutic agent, such as but not limited to sulindac, when administered separately, indicating an additive combination. Without wishing to be bound by any particular theory, it is believed that NSAIDs are associated with GI and cardiovascular toxicity. Budesonide is a corticosteroid with minimal systemic toxicity, as it undergoes extensive first-pass hepatic metabolism by cytochrome P-450 enzymes. Prednisone (a corticosteroid like budesonide) is often used in combination treatment regimens (with chemotherapy) that are usually curative for multiple types of leukemia, lymphoma, and other cancers.

[0193] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0194] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Various changes, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. The following claims define the scope of the invention, and it is intended to cover methods and structures within the scope of these claims, and their equivalents. References [Table 1-1] [Table 1-2] [Table 1-3]

Claims

[Claim 1] The invention described in this specification.

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