Use of cyp26-resistant rar alpha selective agonists in the treatment of cancer

Abstract

Disclosed herein are methods for treating a cancer comprising administering to a subject in need thereof an effective dose of a CYP26-resistant retinoic acid receptor (RAR) alpha (RARα) selective agonist, whereby as a result of the treatment the tumor burden is reduced in the subject and cancer stem cells resident in the bone marrow are substantially reduced.

What is claimed is: 
     
         1 . A method for treating a solid tumor malignancy comprising administering to a subject in need thereof an effective dose of a CYP26-resistant RARα selective agonist, wherein the CYP26-resistant RARα selective agonist is a compound having the structure of formula I,
                     
 wherein R 1  is H or C 1-6  alkyl; R 2  and R 3  are independently H or F; and R 4  is a halogen, 
 whereby as a result of the treatment, the tumor burden is reduced in the subject. 
 
     
     
         2 . The method of  claim 1 , wherein the CYP26-resistant RARα selective agonist is
                     
 
     
     
         3 . The method according to  claim 1 , wherein administration of an effective dose of the RARα agonist results in the elimination of minimal residual disease or cancer stem cells in the bone marrow niche of the subject, thereby improving the disease-free survival of the subject. 
     
     
         4 . The method according to  claim 1 , wherein the solid tumor malignancy is a type of cancer which typically metastasizes to the bone marrow. 
     
     
         5 . The method according to  claim 1 , wherein the solid tumor malignancy is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, brain tumors, bone cancer, or soft tissue sarcoma. 
     
     
         6 . The method according to  claim 1 , further comprising at least one additional anti-cancer agent. 
     
     
         7 . The method according to  claim 6 , wherein the at least one additional anti-cancer agent selected from etoposide, an anthracycline, idarubicin, daunorubicin, mitoxantrone, cytarabine, a combination of an anthracycline, cytarabine and etoposide, a demethylating agent, 5-azacytidine, decitabine, a tyrosine kinase inhibitor, a BCR-ABL inhibitor, a Flt3 inhibitor, a cKit inhibitor, an IDH½ inhibitor, a JAK2 inhibitor, a BTK inhibitor, anti-CD33 monoclonal antibody (mAb), anti-CD20 mAb, anti-CD19 mAb, anti-CD30 mAb, anti-PD1 mAb, anti-CTL4 mAb, lenolidamide, pomalidomide, cyclophosphamide, bevacizumab, vincristine, a corticosteroid, bleomycin, adriamycin, bendamustin, fludarabine, G-CSF, GM-CSF, Epo, a PD1 inhibitor, and a CTL4 inhibitor, and combinations thereof. 
     
     
         8 . A method for treating cancer comprising administering to a subject in need thereof an effective dose of a CYP26-resistant RARα selective agonist, wherein the CYP26-resistant RARα selective agonist is a compound having the structure of formula I,
                     
 wherein R 1  is H or C 1-6  alkyl; R 2  and R 3  are independently H or F; and R 4  is a halogen; 
 and an anti-cancer monoclonal antibody; 
 whereby as a result of the treatment, the cancer burden is reduced in the subject. 
 
     
     
         9 . The method of  claim 1 , wherein the CYP26-resistant RARα selective agonist is
                     
 
     
     
         10 . The method of  claim 8 , wherein the cancer is a hematologic malignancy selected from acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), accelerated CML, CML blast phase (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin’s disease (HD), non-Hodgkin’s lymphoma (NHL), follicular lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, myelodysplastic syndromes (MDS), refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), or a myeloproliferative syndrome. 
     
     
         11 . The method according to  claim 8 , wherein the cancer is a solid tumor malignancy selected from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, brain tumors, bone cancer, or soft tissue sarcoma. 
     
     
         12 . The method according to  claim 8 , wherein the anti-cancer monoclonal antibody is an anti-CD33 monoclonal antibody (mAb), anti-CD20 mAb, anti-CD19 mAb, anti-CD30 mAb, anti-PD1 mAb, or an anti-CTL4 mAb.