Hdac inhibitors and hormone targeted drugs for the treatment of cancer

Abstract

The present invention relates to the methods of treating endocrine-regulated cancers, including hormone resistant cancers, for example. More specifically, the present invention relates to a method of increasing the sensitivity of hormone resistant cancers to hormonal therapeutic agents. In particular embodiments, the present invention concerns delivery of a histone deacetylase inhibitor and a hormone targeted drug to an individual with cancer. In specific embodiments, the histone deacetylase inhibitor and the hormone targeted drug act synergistically to treat the cancer, including by overcoming resistance to a cancer therapy.

1 . A method of treating a hormone resistant cancer in a subject having or suspected of having the hormone resistant cancer, comprising the step of administering to the subject an effective amount of the following:
 a histone deacetylase inhibitor selected from the group consisting of PXD-101, LBH589, FK228, MGCD-0103, R306465, PCI-24781, SB-939, ITF-2357, SAHA, CI-994, and MS-275; and   an aromatase inhibitor.   
     
     
         2 . The method of  claim 1 , wherein the hormone resistant cancer is breast cancer. 
     
     
         3 . The method of  claim 1 , wherein the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, letrozole, formestane, and testolactone. 
     
     
         4 . The method of  claim 2 , wherein the breast cancer is estrogen receptor negative. 
     
     
         5 . The method of  claim 2 , wherein the breast cancer is estrogen receptor positive. 
     
     
         6 . The method of  claim 1 , wherein the histone deacetylase inhibitor and the aromatase inhibitor are administered simultaneously. 
     
     
         7 . The method of  claim 1 , wherein the histone deacetylase inhibitor is administered prior to the administration of the aromatase inhibitor. 
     
     
         8 . The method of  claim 1 , wherein the histone deacetylase inhibitor is administered subsequent to the administration of one or more dose of the aromatase inhibitor. 
     
     
         9 . The method of  claim 1 , wherein the histone deacetylase inhibitor and the aromatase inhibitor act synergistically. 
     
     
         10 . The method of  claim 1 , wherein the histone deacetylase inhibitor is MS-275. 
     
     
         11 . The method of  claim 1 , wherein the hormone resistance is acquired resistance. 
     
     
         12 . A method of treating a hormone resistant cancer in a subject having or suspected of having the hormone resistant cancer, comprising the step of administering to the subject an effective amount of the following:
 a histone deacetylase inhibitor; and   an aromatase inhibitor selected from the group consisting of anastrozole, exemestane, letrozole, formestane, and testolactone.   
     
     
         13 . The method of  claim 12 , wherein the hormone resistant cancer is a hormone resistant breast cancer. 
     
     
         14 . The method of  claim 13 , wherein the breast cancer is estrogen receptor negative. 
     
     
         15 . The method of  claim 13 , wherein the breast cancer is estrogen receptor positive. 
     
     
         16 . The method of  claim 12 , wherein the histone deacetylase inhibitor is SAHA, CI-994, PXD-101, LBH589, FK228, MGCD-0103, R306465, PCI-24781, SB-939, ITF-2357, and MS-275. 
     
     
         17 . The method of  claim 12 , wherein the histone deacetylase inhibitor is MS-275. 
     
     
         18 . The method of  claim 12 , wherein the hormone resistance is acquired resistance. 
     
     
         19 . A method of treating a hormone resistant breast cancer in a subject having or suspected of having the hormone resistant breast cancer, comprising the step of administering to the subject an effective amount of the following:
 a histone deacetylase inhibitor selected from the group consisting of SAHA, CI-994, PXD-101, LBH589, FK228, MGCD-0103, R306465, PCI-24781, SB-939, ITF-2357, and MS-275; and   an aromatase inhibitor selected from the group consisting of anastrozole, exemestane, letrozole, formestane, testolactone, and a combination thereof.   
     
     
         20 . The method of  claim 19 , wherein the breast cancer is ER−, PR+. 
     
     
         21 . The method of  claim 19 , wherein the breast cancer is ER−, PR− and Her2+. 
     
     
         22 . The method of  claim 19 , wherein the breast cancer is ER−, PR− and Her2−. 
     
     
         23 . The method of  claim 19 , wherein the histone deacetylase inhibitor is MS-275. 
     
     
         24 . The method of  claim 19 , wherein the hormone resistance is acquired resistance. 
     
     
         25 . A method of inhibiting growth of a cell comprising contacting the cell with an aromatase inhibitor and a histone deacetylase inhibitor, each in an effective amount to inhibit growth of said cell, wherein the histone deacetylase inhibitor is selected from the group consisting of PXD-101, LBH589, FK228, MGCD-0103, R306465, PCI-24781, SB-939, ITF-2357, SAHA and CI-994 and MS-275. 
     
     
         26 . The method of  claim 25 , wherein the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, letrozole, formestane, testolactone, and a combination thereof. 
     
     
         27 . The method of  claim 25 , wherein the histone deacetylase inhibitor is MS-275. 
     
     
         28 . The method of  claim 25 , wherein the hormone resistance is acquired resistance. 
     
     
         29 . A method of inhibiting growth of a cell comprising contacting the cell with an aromatase inhibitor and a histone deacetylase inhibitor, each in an effective amount to inhibit growth of said cell, wherein the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, letrozole, formestane, testolactone, and a combination thereof. 
     
     
         30 . The method of  claim 29 , wherein the cell is a refractory cancer cell and the hormone resistance is acquired resistance. 
     
     
         31 . The methods of  claim 29 , wherein the histone deacetylase inhibitor increases the expression of an estrogen receptor on the cell. 
     
     
         32 . The method of  claim 29 , wherein the histone deacetylase inhibitor increases the expression or activity of aromatase in the cell. 
     
     
         33 . The method of  claim 29 , wherein the contacting occurs in vivo. 
     
     
         34 . The method of  claim 29 , wherein the histone deacetylase inhibitor is MS-275. 
     
     
         35 . The method of  claim 29 , wherein the hormone resistance is acquired resistance. 
     
     
         36 . A method of treating a hormone resistant cancer in a subject having or suspected of having the hormone resistant cancer, comprising the step of administering to the subject an effective amount of the following:
 a histone deacetylase inhibitor; and   an anti-androgen, wherein the anti-androgen is not a 17alpha-hydroxylase-C17,20-lyase inhibitor or a 5-reductase inhibitor.   
     
     
         37 . The method of  claim 36 , wherein the hormone resistant cancer is prostate cancer. 
     
     
         38 . The method of  claim 36 , wherein the histone deacetylase inhibitor is a selective histone deacetylase inhibitor. 
     
     
         39 . The method of  claim 36 , wherein the histone deacetylase inhibitor is selected from the group consisting of SAHA, CI-994, PXD-101, LBH589, FK228, MGCD-0103, R306465, PCI-24781, SB-939, ITF-2357, and MS-275. 
     
     
         40 . The method of  claim 36 , wherein the anti-androgen is selected from the group consisting of spironolactone (Aldactone, Spiritone; Novo-Spiroton, Spiractin, Verospiron or Berlactone), cyproterone acetate (Androcur, Climen, Diane 35, Ginette 35), flutamide (Eulexin), nilutamide (Anandron, Nilandron), bicalutamide (Casodex) and a combination thereof. 
     
     
         41 . The method of  claim 36 , wherein the histone deacetylase inhibitor and the anti-androgen are administered simultaneously. 
     
     
         42 . The method of  claim 36 , wherein the histone deacetylase inhibitor is administered prior to the administration of the anti-androgen. 
     
     
         43 . The method of  claim 36 , wherein the histone deacetylase inhibitor and the anti-androgen act synergistically. 
     
     
         44 . The method of  claim 36 , wherein the hormone resistance is acquired resistance.