Methods and compositions for modulating cancer stem cells

Abstract

Disclosed are compositions and methods that use lysine demethylase inhibitors for inhibiting the growth of cancer stem cells or tumor initiating cells, for enhancing the biological effects of chemotherapeutic drugs or irradiation on cancer cells and/or for preventing cancer recurrence.

1 - 98 . (canceled) 
     
     
         99 . A method for treating a metastatic breast cancer in a human subject, wherein the metastatic breast cancer comprises mesenchymal cancer stem cells (CSCs) and non-CSC tumor cells, the method comprising concurrently administering to the subject an LSD inhibitor in an effective amount to inhibit formation, proliferation, survival, viability, maintenance or epithelial-to-mesenchymal transition (EMT) of the mesenchymal CSCs of the cancer or to stimulate mesenchymal-to-epithelial transition (MET) of the mesenchymal CSCs of the cancer, and a cancer therapy or agent that inhibits proliferation, survival or viability of the non-CSC tumor cells, to thereby treat the metastatic breast cancer. 
     
     
         100 . The method according to  claim 99 , wherein the LSD inhibitor is an LSD1 inhibitor. 
     
     
         101 . The method according to  claim 100 , wherein the LSD1 inhibitor is an MAO inhibitor. 
     
     
         102 . The method according to  claim 100 , wherein the LSD1 inhibitor is an MAO inhibitor selected from clorgyline, pargyline and phenelzine, or derivatives thereof. 
     
     
         103 . The method according to  claim 99 , wherein the LSD inhibitor is a selective LSD1 inhibitor. 
     
     
         104 . The method according to  claim 103 , wherein the selective LSD1 inhibitor is a phenylcyclopropylamine derivative. 
     
     
         105 . The method according to  claim 103 , wherein the selective LSD1 inhibitor is a phenylcyclopropylamine derivative represented by formula XII: 
       
         
           
           
               
               
           
         
         wherein: 
         Ar 1  is a 5 to 7 membered aryl or heteroaryl ring; 
         Ar 2  and Ar 3  are each independently selected from a 5 to 7 membered aryl or heteroaryl ring, optionally substituted with 1 to 3 substituents; 
         R 1  and R 2  are independently selected from hydrogen and hydroxyl or taken together R 1  and R 2  form ═O, ═S or ═NR 3 ; 
         R 3  is selected from hydrogen, —C 1-6 alkyl or OH; 
         m is an integer from 1 to 5; and 
         n is an integer from 1 to 3; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         106 . The method according to  claim 103 , wherein the selective LSD1 inhibitor is a phenylcyclopropylamine derivative represented by formula XIIa: 
       
         
           
           
               
               
           
         
         wherein: 
         Ar 2  and Ar 3  are each independently selected from a 5 to 7 membered aryl or heteroaryl ring, optionally substituted with 1 to 3 substituents. 
       
     
     
         107 . The method according to  claim 103 , wherein the selective LSD1 inhibitor is a phenylcyclopropylamine derivative represented by formula XIIa: 
       
         
           
           
               
               
           
         
         wherein: 
         Ar 2  and Ar 3  are selected from the following table: 
       
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Ar 2   
                   Ar 3   
                 
                     
                     
                 
                     
                   phenyl 
                   phenyl 
                 
                     
                   4-methylphenyl 
                   phenyl 
                 
                     
                   4-t-butylphenyl 
                   phenyl 
                 
                     
                   4-chlorophenyl 
                   phenyl 
                 
                     
                   4-fluorophenyl 
                   phenyl 
                 
                     
                   4-phenyl-phenyl 
                   Phenyl 
                 
                     
                   4-trifluoromethylphenyl 
                   Phenyl 
                 
                     
                   3-(2-aminoethylcarbamoyl)phenyl 
                   Phenyl 
                 
                     
                   3-(piperazine-1-carbonyl)phenyl 
                   Phenyl 
                 
                     
                   4-phenyl-phenyl 
                   4-methylphenyl 
                 
                     
                   4-phenyl-phenyl 
                   4-fluorophenyl 
                 
                     
                   4-phenyl-phenyl 
                   4-phenyl-phenyl 
                 
                     
                   4-phenyl-phenyl 
                   4-t-butylphenyl 
                 
                     
                   4-phenyl-phenyl 
                   3-methylphenyl 
                 
                     
                   4-phenyl-phenyl 
                   3-fluorophenyl 
                 
                     
                   4-phenyl-phenyl 
                   3-phenyl-phenyl 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         108 . The method according to  claim 99 , wherein the cancer therapy or agent is selected from radiotherapy, surgery, chemotherapy, hormone ablation therapy, pro-apoptosis therapy, stem cell transplant and immunotherapy. 
     
     
         109 . The method according to  claim 108 , wherein the immunotherapy comprises antibody therapy. 
     
     
         110 . The method according to  claim 108 , wherein the cancer therapy or agent targets rapidly dividing cells or disrupts the cell cycle or cell division. 
     
     
         111 . The method according to  claim 108 , wherein the chemotherapy comprises a taxoid. 
     
     
         112 . The method according to  claim 111 , wherein the taxoid is paclitaxel or docetaxel. 
     
     
         113 . The method according to  claim 111 , wherein the taxoid is docetaxel. 
     
     
         114 . The method according to  claim 99 , wherein the CSCs are capable of giving rise to non-CSC tumor cells that are hormone-resistant. 
     
     
         115 . The method according to  claim 99 , wherein the non-CSC tumor cells are hormone receptor negative for at least one hormone receptor selected from an estrogen receptor (ER) and a progesterone receptor (PR).