Posted December 18, 2014
Marianne Sadar, PhD, B. C. Cancer Agency, Vancouver, Canada
Stephen R. Plymate, MD, University of Washington
The androgen receptor (AR) plays an important role in prostate cancer (PCa) since it mediates the effects of testosterone, the sex hormone that drives growth and proliferation. Therapies designed to inhibit testosterone production or block AR signaling are often used to treat advanced prostate cancer. Current hormone-based therapies specifically target one end of the AR, the C-terminal domain. Given that many cases of castrate resistant prostate cancer contain variants of the AR protein that lack this C-terminal end, there is a need for drugs that can target the N-terminal domain instead, which is present in both the regular AR and AR variants.
With this in mind, two collaborating interdisciplinary teams headed by Dr. Marianne Sadar at the B. C. Cancer Agency in Vancouver, Canada and Dr. Stephen R. Plymate at the University of Washington, Seattle, USA, were funded by the FY09 Synergistic Idea Development Award mechanism to investigate small molecule inhibitors to the AR N-terminal region. An optimal inhibitor would target the N-terminal domain, and upon binding change the shape of the AR to prevent interactions with other proteins, resulting in loss of activity and ultimately leading to arrested cellular growth.
Dr. Sadar had received prior PCRP support that led to the identification of an experimental drug, EPI-001, which was isolated from a marine sponge and demonstrated antitumor activity in human prostate cancer xenografts (PC040768 and PC060451). The synergy of Dr. Sadar's biochemical and biological expertise with this new class of AR inhibitors and Dr. Plymate's translational experience with preclinical models and clinical trial design enabled the team to further investigate EPI-001, and the analogue, EPI-002, which binds to both the full length AR and AR splice variants. Pre-clinical work to date includes optimizing the formulation for oral delivery, as well as, the generation of the safety and toxicity profiles for EPI-002. The research team envisions taking an analogue of EPI compound forward into phase I clinical trials in the near future.
The EPI-class of compounds is the first to show promise in inhibiting all forms of the AR, including those that lead to resistance of currently available therapies. With further development, EPI compounds could lead to next generation clinical agents to combat the highly lethal castration resistant form of the disease.
Public and Technical Abstracts:
Previous Related Support:
Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, Tien AH, Tavekoli I, Yang YC, Haile S, Watt K, McEwan IJ, Plymate S, Andersen RJ, Sadar MD. "An androgen receptor N-terminal domain antagonist for treating prostate cancer" J. Clin. Invest. 2013; 123(7):2948-2960.
Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T, Yang YC, Bañuelos CA, Williams DE, McEwan IJ, Wang Y, Sadar MD. "Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor." Cancer Cell. 2010; Jun 15; 17(6):535-46