S31-2 AR-V7 in Prostate Cancer: Mechanisms of Activation and Search for New Antagonists

Program: Symposia
Session: S31-AR and Coactivators in Prostate Cancer
Sunday, June 16, 2013: 4:00 PM-5:30 PM
Presentation Start Time: 4:30 PM
Room 256 (Moscone Center)
Marco Marcelli*
Baylor Coll of Med VAMC, Houston, TX
Talk Description:

Earlier observations that lab-generated ligand binding domain (LBD)-truncated AR (androgen receptor) are transcriptionally active in the absence of agonist have found clinical relevance in castration resistant prostate cancer (CRPC) with the discovery of the carboxy-terminally truncated constitutively active AR variants (AR-Vs). AR-Vs are thought to accumulate in response to tumor environment stress created by androgen deprivation therapy (ADT), and their constitutive activity offers a simple and uniform explanation of why PC evolves into treatment-resistant CRPC. From a teleological point of view, androgen-starved PC cells overexpress AR-V7, the primary truncated AR, to survive and proliferate despite the altered endocrine milieu created by ADT. The process of ligand-independent activation of AR-V7 in CRPC proceeds through outlaw regulatory steps that result in steady state protein levels, constitutive nuclear localization and persistent transcriptional activity. Unraveling the mechanism of constitutive activation for AR-V7 and finding novel inhibitors is exceedingly important since all classic AR antagonists, including Enzalutamide, fail to suppress AR-V7 activation, and thousands of CRPC patients die each year. We will describe our effort to identify the pathways involved with AR-V7 activity, and new antagonists targeting the activity of this molecule.