Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor
Androgen receptor (AR) is a transcription factor that plays an important role in prostate cancer. We identified EPI-001 as a small molecule that inhibits transactivation of the AR amino-terminal domain (NTD). The advantages of EPI-001 are: (1) its mechanism is unique from antiandrogens that target the C-terminal ligand-binding domain (LBD) and fail presumably due to gain-of-function mutations in the LBD, or expression of constitutively active splice variants; (2) it does not appear to be toxic in the therapeutic dose range in vivo; and (3) currently there are no curative treatment options for castration- recurrent prostate cancer (CRPC). These findings suggest that the AR NTD is a promising target to develop therapeutics for the treatment of CRPC.
Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor. Raymond J. Andersen, Nasrin R. Mawji, Jun Wang, Gang Wang, Simon Haile, Jae-Kyung Myung, Kate Watt, Teresa Tam, Yu Chi Yang, Carmen A. Bañuelos, David E. Williams, Iain J. McEwan, Yuzhou Wang, Marianne D. Sadar Cancer Cell, Volume 17, Issue 6, 535-546, 15 June 2010
This research was supported by grants from the Canadian Institutes of Health Science, National Cancer Institute of Canada (R.J.Andersen), and the U.S. Army Medical Research and Materiel Command Prostate Cancer Research Program (M.D.Sadar). We are grateful to Country Meadows Senior Men’s Golf Charity Classic and the FORE PAR Prostate Awareness Research Charity Golf Classic for their financial support to purchase essential equipment. The article is dedicated to men who have fought but succumbed to CRPC (castrate-resistant prostate cancer).
In the same issue of Cancer Cell, A Previews Article by Timothy C. Thompson highlights the importance of this research (Cancer Cell 17, June 15, 2010 525-526) pointing out "it is a rare occasion in prostate cancer research when such a unique and promising therapeutic agent for advanced prostate cancer is developed. We all wait with interest the further preclinical and possible clinical testing of EPI-001 or its derivative(s).