Accession Number:

ADA590496

Title:

Inhibition of the Androgen Receptor Amino-Terminal Domain by a Small Molecule as Treatment for Castrate-Resistant Prostate Cancer

Descriptive Note:

Annual rept. 15 Sep 2012-14 Sep 2013

Corporate Author:

WASHINGTON UNIV SEATTLE

Personal Author(s):

Report Date:

2013-10-01

Pagination or Media Count:

31.0

Abstract:

-Purpose 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 3We have completed the EPI-002 treatment in 5 xenograft lines in the second year of this study. These were done following castration and in castrate resistant growth states. Tasks 4 and 5 We have measured intratumoral androgen and found that they have a major impact on EPI 2 response. IHC analysis of these tumors. A distinct AR variant transcriptome has been identified is suppressed by EPI-002. Findings We have clearly shown that EPI-001 and -002 can suppress the growth of AR-variant driven prostate cancers. We have also shown that Intratumoral androgens play a major role in determining response to N-terminal inhibition. Significance Based on these studies to this point as formulation of the compounds is optimized we would hope to move forward with application for FDA approval for Phase 1 clinical trials.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE