Combination of Anti-Clusterin Oligonucleotide with HSP90 Inhibitor for the Treatment of Prostate Cancer

Abstract

The present invention provides a method for treating a mammalian subject affected by prostate cancer comprising i) an oligonucleotide which reduces clusterin expression and ii) a Heat Shock Protein 90 (Hsp90) inhibitor each in an amount that when in combination with the other is effective to treat the mammalian subject. The present invention also provides pharmaceutical compositions comprising an amount of an oligonucleotide which reduces clusterin expression, and a Hsp90 inhibitor for use in treating a mammalian subject affected by prostate cancer. Also provided are oligonucleotides which reduce clusterin expression for use in combination with a Hsp90 inhibitor in treating a mammalian subject affected by prostate cancer, and a composition for treating a mammalian subject affected by prostate cancer comprising i) an oligonucleotide which reduces clusterin expression and ii) a Hsp90 inhibitor each in an amount that when in combination with the other is effective to treat the mammalian subject.

1 - 33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising an amount of an oligonucleotide which reduces clusterin expression, and a Hsp90 inhibitor, wherein the oligonucleotide is an antisense or RNAi oligonucleotide the reduces clusterin expression, and the Hsp90 inhibitor is 4-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(4-hydroxy-cyclohexylamino)-benzamide, or a pharmaceutically acceptable salt thereof, or a prodrug that is metabolized to release 4-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(4-hydroxy-cyclohexylamino)-benzamide. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the oligonucleotide is an antisense oligonucleotide. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the antisense oligonucleotide comprises one of SEQ ID NOs 3, 4 and 11. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the antisense oligonucleotide comprises SEQ ID NO: 3. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the antisense oligonucleotide is modified to enhance in vivo stability relative to an unmodified oligonucleotide of the same sequence. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the oligonucleotide is custirsen. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the Hsp90 inhibitor is Hsp90i-2-PRO. 
     
     
         41 . The pharmaceutical composition of  claim 37 , wherein the Hsp90 inhibitor is Hsp90i-2-PRO. 
     
     
         42 . The pharmaceutical composition of  claim 35 , wherein the Hsp90 inhibitor is Hsp90i-2-PRO. 
     
     
         43 . The pharmaceutical composition of  claim 34 , wherein the Hsp90 inhibitor is Hsp90i-2-PRO.