Compositions for Modulating Cancer Stem Cells and Uses Therefor

Abstract

Disclosed are compositions and methods for modulating cancer stem cells. More particularly, the present invention discloses the use of lysine demethylase (LSD) inhibitors and protein kinase C theta inhibitors (PKC-θ) for inhibiting the growth of LSD- and/or PKC-θ-overexpressing cells including cancer stem cells, for enhancing the biological effects of chemotherapeutic drugs or irradiation on cancer cells, for treating cancer, including non-metastatic and metastatic cancer and/or for preventing cancer recurrence.

1 - 22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising a selective LSD1 inhibitor, a selective PKC-θ inhibitor and a pharmaceutically acceptable carrier. 
     
     
         24 . A pharmaceutical composition according to  claim 23 , wherein the LSD1 inhibitor is a MAO inhibitor. 
     
     
         25 . A pharmaceutical composition according to  claim 24 , wherein the MAO inhibitor is selected from clorgyline, pargyline and phenelzine, or derivatives thereof. 
     
     
         26 . A pharmaceutical composition according to  claim 23 , wherein the 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. 
       
     
     
         27 . A pharmaceutical composition according to  claim 26 , wherein the LSD1 inhibitor is a phenylcyclopropylamine derivative represented by formula XIIa: 
       
         
           
           
               
               
           
         
         wherein: 
         Ar 2  and Ar 3  are as defined in  claim 26 . 
       
     
     
         28 . A pharmaceutical composition according to  claim 27 , wherein Ar 2  and Ar 3  are selected according to 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 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         29 . A pharmaceutical composition according to  claim 27 , wherein the LSD1 inhibitor is represented by the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         30 . A pharmaceutical composition according to  claim 23 , wherein the PKC-θ inhibitor is a pyrazolopyridine compound represented by formula (XXXIIIa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is independently F, Cl or CF 3 ; and 
         R 2  is independently H, F, Cl, OH, CN or CH 2 OH. 
       
     
     
         31 . A pharmaceutical composition according to  claim 30 , wherein the pyrazolopyridine compound is represented by formula (XXXIIIb): 
       
         
           
           
               
               
           
         
       
     
     
         32 . A pharmaceutical composition according to  claim 23 , further comprising a cancer therapy agent. 
     
     
         33 . A pharmaceutical composition according to  claim 32 , wherein the cancer therapy agent is a chemotherapeutic agent that targets rapidly dividing cells or disrupts the cell cycle or cell division. 
     
     
         34 . A pharmaceutical composition according to  claim 32 , wherein the cancer therapy agent is a chemotherapeutic agent inhibits cancer cell invasion. 
     
     
         35 . A pharmaceutical composition according to  claim 32 , wherein the cancer therapy agent is a taxoid. 
     
     
         36 . A pharmaceutical according to  claim 35 , wherein the taxoid is paclitaxel or docetaxel. 
     
     
         37 . A pharmaceutical according to  claim 35 , wherein the taxoid is docetaxel. 
     
     
         38 . A pharmaceutical composition according to  claim 32 , wherein the cancer therapy agent is an immunotherapeutic agent. 
     
     
         39 . A pharmaceutical composition according to  claim 38 , wherein the immunotherapeutic agent is an antibody that target tumor cells. 
     
     
         40 . A pharmaceutical composition according to  claim 38 , wherein the immunotherapeutic agent is an antibody inhibits growth factor function. 
     
     
         41 . A pharmaceutical composition according to  claim 38 , wherein the immunotherapeutic agent is an immune effector cell that targets tumor cells. 
     
     
         42 . A pharmaceutical composition according to  claim 38 , wherein the immunotherapeutic agent is an immune effector cell that targets tumor cells, wherein the immune effector cells is a cytotoxic T cell or natural killer cell.