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 multiple myeloma consisting of administering to a subject in need thereof an effective dose of a CYP26-resistant retinoic acid receptor alpha (RARα) selective agonist and an immunotherapeutic monoclonal antibody (mAb), 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 
         optionally, at least one additional anti-cancer agent selected from the list consisting of etoposide, an anthracycline, idarubicin, daunorubicin, mitoxantrone, cytarabine, a combination of an anthracycline, cytarabine and etoposide, a demethylating agent, 5-azacytidine, decitabine, a proteasome inhibitor, bortezomib, a tyrosine kinase inhibitor, a BCR-ABL inhibitor, a Flt3 inhibitor, a cKit inhibitor, an IDH1/2 inhibitor, a JAK2 inhibitor, a BTK inhibitor, lenalidomide, pomalidomide, cyclophosphamide, bevacizumab, vincristine, a corticosteroid, bleomycin, adriamycin, bendamustin, fludarabine, G-CSF, GM-CSF, Epo, and combinations thereof, 
         whereby as a result of the treatment the tumor burden, including multiple myeloma (MM) B cell burden, is reduced in the subject. 
       
     
     
         2 . The method according to  claim 1 , consisting of administration of the effective dose of the CYP26-resistant RARα selective agonist, immunotherapeutic mAb, and the at least one additional anti-cancer agent. 
     
     
         3 . The method according to  claim 1 , wherein the CYP26-resistant RARα selective agonist is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method according to  claim 1 , wherein the immunotherapeutic mAb is an anti-CD33 mAb. 
     
     
         5 . The method according to  claim 1 , wherein the immunotherapeutic mAb is an anti-CD20 mAb. 
     
     
         6 . The method according to  claim 1 , wherein the immunotherapeutic mAb is an anti-CD19 mAb. 
     
     
         7 . The method according to  claim 1 , wherein the immunotherapeutic mAb is an anti-CD30 mAb. 
     
     
         8 . The method according to  claim 1 , wherein the immunotherapeutic mAb is an anti-PD1 mAb. 
     
     
         9 . The method according to  claim 1 , wherein the immunotherapeutic mAb is an anti-CTLA4 mAb. 
     
     
         10 . The method according to  claim 2 , wherein the at least one additional anti-cancer agent comprises a proteasome inhibitor. 
     
     
         11 . The method according to  claim 10 , wherein the proteasome inhibitor is bortezomib. 
     
     
         12 . The method according to  claim 2 , wherein the at least one additional anti-cancer agent comprises lenalidomide. 
     
     
         13 . The method according to  claim 2 , wherein the at least one additional anti-cancer agent comprises pomalidomide. 
     
     
         14 . The method according to  claim 1 , wherein the subject has minimal residual disease. 
     
     
         15 . The method according to  claim 1 , wherein administration of an effective dose of the CYP26-resistant RARα selective agonist results in sensitization of minimal residual disease to the immunotherapeutic mAb or the at least one additional anticancer agent, whereby combination of the CYP26-resistant RARα selective agonist with the immunotherapeutic mAb or the at least one additional anticancer agent results in improvement of disease-free survival of the subject.