Methods for treating androgen receptor dependent disorders including cancers

Abstract

The invention provides the combination use of antisense oligomers targeting androgen receptor mRNA and androgen receptor binding inhibitors that reduce androgen receptor activity for the treatment of androgen receptor related medical disorders, such as cancers, particularly prostate cancers and breast cancers.

What is claimed is: 
     
         1 . A method for treating an androgen receptor dependent hyperproliferative disorder in a mammal, comprising the steps of:
 administering to a mammal in need of treatment for an androgen receptor dependent hyperproliferative disorder in amounts therapeutically effective in combination,
 (a) an antisense oligomer selected from the group consisting of: 
   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 58) 
                 
                     
                   5′-A s   Me C s   Me C s a s a s g s t s t s t s c s t s t s c s A s G s   Me C-3′; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 77) 
                 
                     
                   5′- Me C s   Me C s   Me C s a s a s g s g s c s a s c s t s g s c s A s G s A-3′, 
                 
             
                
                
                
                
                
                
               
            
           
         
         
           wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript “s” denotes a phosphorothioate linkage, and  Me C denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base, or a conjugate of said oligomer, or a pharmaceutically acceptable salt of said compound or said conjugate; and 
           (b) a compound selected from the group consisting of: 
         
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt of said compound. 
         
       
     
     
         2 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         3 . The method of  claim 2 , wherein the androgen receptor dependent hyperproliferative disorder is selected from the group consisting of prostate cancer, benign prostatic hyperplasia and breast cancer. 
     
     
         4 . The method of  claim 3 , wherein the androgen receptor dependent hyperproliferative disorder is prostate cancer. 
     
     
         5 . The method of  claim 4 , wherein the prostate cancer is castration-resistant prostate cancer. 
     
     
         6 . The method of  claim 4 , wherein the prostate cancer is advanced prostate cancer. 
     
     
         7 . The method of  claim 3 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 3 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 3 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A kit comprising:
 (a) a pharmaceutical composition comprising an antisense oligomer selected from the group consisting of:   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 58) 
                 
                     
                   5′-A s   Me C s   Me C s a s a s g s t s t s t s c s t s t s c s A s G s   Me C-3′; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 77) 
                 
                     
                   5′- Me C s   Me C s   Me C s a s a s g s g s c s a s c s t s g s c s A s G s A-3′, 
                 
             
                
                
                
                
                
                
               
            
           
         
         wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript “s” denotes a phosphorothioate linkage, and  Me C denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base, or a conjugate of said oligomer, or a pharmaceutically acceptable salt of said compound or said conjugate; and 
         (b) a pharmaceutical composition comprising a compound selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of said compound. 
       
     
     
         11 . A method for treating an androgen receptor dependent hyperproliferative disorder in a mammal, comprising the steps of:
 administering to a mammal in need of treatment for an androgen receptor dependent hyperproliferative disorder in amounts therapeutically effective in combination,
 (a) an antisense oligomer selected from the group consisting of: 
   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 58) 
                 
                     
                   5′-A s   Me C s   Me C s a s a s g s t s t s t s c s t s t s c s A s G s   Me C-3′; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 77) 
                 
                     
                   5′- Me C s   Me C s   Me C s a s a s g s g s c s a s c s t s g s c s A s G s A-3′, 
                 
             
                
                
                
                
                
                
               
            
           
         
         
           wherein uppercase letters denote beta-D-oxy-LNA monomers and lowercase letters denote DNA monomers, the subscript “s” denotes a phosphorothioate linkage, and  Me C denotes a beta-D-oxy-LNA monomer containing a 5-methylcytosine base, or a conjugate of said oligomer, or a pharmaceutically acceptable salt of said compound or said conjugate; and 
           (b) a non-steroidal antiandrogen compound or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         12 . The method of  claim 11 , wherein the mammal is a human. 
     
     
         13 . The method of  claim 12 , wherein the non-steroidal antiandrogen compound is bicalutamide. 
     
     
         14 . The method of  claim 13 , wherein the androgen receptor dependent hyperproliferative disorder is selected from the group consisting of prostate cancer, benign prostatic hyperplasia and breast cancer. 
     
     
         15 . The method of  claim 14 , wherein the androgen receptor dependent hyperproliferative disorder is prostate cancer. 
     
     
         16 . The method of  claim 15 , wherein the prostate cancer is castration-resistant prostate cancer.