Ar+ breast cancer treatment methods

Abstract

A method for treating AR+ breast cancer in a subject comprising administering to the subject an AR agonist (e.g., SARMs such as RAD140), or in combination with one or more therapeutic agents selected from the group consisting of cdk4/6 inhibitors, m-TOR inhibitors, PI3k inhibitors, PARP inhibitors, BCL-2 inhibitors, and MCL-1 inhibitors.

1 . A method of treating AR+/ER+ breast cancer in a subject comprising administering to the subject a compound according to Formula I 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salts thereof, or a pharmaceutically acceptable solvate thereof, wherein:
 R x =CN; 
 R y =CF 3  or Cl; 
 R z =CH 3 , CH 2 CH 3 , or Cl; or 
 R y  and R z  together form: 
 
       
         
           
           
               
               
           
         
         R a′  is H, F, Cl, CN, OH or OSO 3 —; and 
         R 1  and R 2  are each independently selected from the group consisting of hydrogen and methyl. 
       
     
     
         2 . The method according to  claim 1  wherein the compound according to Formula I is Compound II: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 1  wherein the compound according to Formula I is RAD140 (Compound III): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method according to  claim 1  wherein the administration is via an oral route. 
     
     
         5 . The method according to  claim 1  wherein said subject is a woman. 
     
     
         6 . The method according to  claim 5  wherein said woman is a premenopausal woman. 
     
     
         7 . The method according to  claim 5  wherein said woman is a postmenopausal woman. 
     
     
         8 . The method of  claim 1  wherein the subject is treated in an adjuvant setting. 
     
     
         9 . The method of  claim 1  wherein the subject has had disease progression after treatment with one or more endocrinological agents. 
     
     
         10 . The method according to  claim 9  wherein said one or more endorinological agents are selected from the group consisting of SERMs, SERDs, progestins, aromatase inhibitors, and combinations thereof. 
     
     
         11 . The method of  claim 1  wherein said subject has had disease progression after treatment with one or more agents selected from the group consisting of CDK4/6 inhibitors, mTOR inhibitors, BCL-2 inhibitors, PI3K inhibitors, and combinations thereof. 
     
     
         12 . The method according to  claim 1  wherein said breast cancer is localized, advanced or metastatic breast cancer. 
     
     
         13 . The method according to  claim 3  wherein said RAD140 is dosed between 10 and 500 mg, 10 mg and 250 mg, or 25 mg and 250 mg per day. 
     
     
         14 . The method according to  claim 13  wherein the dose is once per day. 
     
     
         15 . The method according to  claim 1  wherein the subject expresses ESR1 comprising one or more mutations. 
     
     
         16 . The method according to  claim 15  wherein said mutation affects the binding affinity of ligands compared to non-mutated ESR1. 
     
     
         17 . The method according to  claim 16  wherein said mutation results in reduced estradiol affinity for the mutated ESR1 compared to the non-mutated ESR1. 
     
     
         18 . The method according to  claim 15  wherein said mutation signals ligand dependently or ligand independently through the ESR1 pathway. 
     
     
         19 . The method according to  claim 15  wherein said mutation results in a fusion protein containing at least 10 continuous amino acids from a sequence of a non-mutated ESR1 and at least 10 continuous amino acids from another human protein. 
     
     
         20 . The method according to  claim 15  wherein said mutation results in ESR1 missing 10 or more consecutive amino acids from its normal (non-mutated) ligand binding domain amino acid sequence. 
     
     
         21 . The method according to  claim 15  wherein said mutation comprises one or more mutations selected from the group consisting of ESR1-AKAP12, ESR1-CCDC170, ESR1-YAP1, ESR1-POLH, ESR1-PCDH11X, and combinations thereof. 
     
     
         22 . The method according to  claim 1  wherein the treatment further comprises the administration of a CDK4/6 inhibitor. 
     
     
         23 . The method according to  claim 22  wherein said CDK4/6 inhibitor has an IC 50  of <100 nM against CDK4 and CDK6. 
     
     
         24 . The method according to  claim 1  wherein said CDK4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib, trilaciclib and abemaciclib. 
     
     
         25 . The method according to  claim 1  wherein said treatment further comprises the administration of an mTOR inhibitor. 
     
     
         26 . The method of  claim 25  wherein said mTOR inhibitor is selected from the group consisting of sirolimus, temsirolimus, everolimus, ridafarolimus, and MLN0128. 
     
     
         27 . The method of  claim 1  further comprising the administration of a PI3K inhibitor. 
     
     
         28 . The method of  claim 27  wherein said PI3K inhibitor is BEZ235, GDC-0980, BKM120, GDC-0941, BYL719, GDC-0032, MK2206, GDC-0068, GSK2110183, GSK2141795, AZD5363, AZD2014, MLN0128 or CC-223. 
     
     
         29 . The method according to  claim 1  further comprising the administration of a PARP inhibitor. 
     
     
         30 . The method of  claim 29  wherein said PARP inhibitor is talazoparib, veliparib, niraparib, beigene290, E7449, KX01, ABT767, CK102, JPI289, KX02, IMP4297, SC10914, NT125, PJ34, VPI289 or ANG-3186. 
     
     
         31 . The method according to  claim 1  further comprising the administration of a MCL-1 inhibitor. 
     
     
         32 . The method according to  claim 31  wherein said MCL-1 inhibitor is 7-(5-((4-(4-(4-(N,N-Dimethylsulfamoyl)piperazin-1-yl)phenoxy)methyl)-1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-morpholinoethyl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic Acid, S63845, omacataxine, seliciclib, UMI-77, AT101, sabutoclax or TW-37. 
     
     
         33 . The method according to  claim 1  further comprising the administration of a BCL-2 inhibitor. 
     
     
         34 . The method of  claim 33  wherein said BCL-2 inhibitor is venetoclax, navitoclax, ABT737, G3139 or S55746. 
     
     
         35 . The method according  claim 1  wherein said treating is first line treatment in a non-adjuvant setting. 
     
     
         36 . A kit comprising an AR agonist according to  claim 1  and one or more agents selected from the group consisting of PARP inhibitors, mTOR inhibitors, CDK4/6 inhibitors, PI3K inhibitors, BCL2 inhibitors, MCL-1 inhibitors, and combinations thereof. 
     
     
         37 - 104 . (canceled)