Inhibition of the Androgen Receptor Amino-Terminal Domain by a Small Molecule as Treatment for Castrate-Resistant Prostate Cancer
Abstract
The hypothesis of this study is that EPI-001 that targets the AR NTD will inhibit AR-driven recurrence of prostate cancer resistant to current methods of androgen deprivation or blockade. Scope: Aim 1 will determine the impact of EPI-001 on castration sensitive tumor regression and re-growth in LuCap xenografts and on growth of their castration resistant forms. Aim 2 will examine the impact of EPI-001 on castration sensitive and castration resistant growth of tumors with differing tumor androgen levels and differing ratios of ARv567es to full-length AR. Aim 3 will elucidate the specific molecular mechanisms by which EPI-001 inhibits the activity of full-length AR and truncated ARv567es variants using in vitro models. Progress: Tasks 1 and 3:We have completed the EPI-001 treatment in 5 xenograft lines in the first year of this study. These were done following castration and in castrate resistant growth states. Tasks 4 and 5: We have begun to measure intratumoral androgens and begin IHC analysis of these tumors. A distinct AR variant transcriptome has been identified and reported. Findings: We have clearly shown that EPI-001 can suppress the growth of AR-variant driven prostate cancers. We have also shown that tumors with both AR-full length and variant receptors may respond to both N- and C-terminal agents. Significance: EPI-001 is effective at inhibiting castration resistant prostate cancer driven by AR-variants in vivo. This class of componds should be considered for clinical trial.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2012
- Accession Number
- ADA566784
Entities
People
- Stephen R Plymate
Organizations
- Seattle University