Abstract 610: Preclinical evaluation of novel androgen receptor N-terminal domain inhibitor EPI-002 for the treatment of castration-resistant prostate cancer
Authors: Yang Yu Chi (Kevin) , Mawji Nasrin (Rina) , Wang Jean , Sadar Marianne 
Published: May 2015

Abstract
Background:
Androgen receptor (AR) is a ligand-activated transcription factor that plays critical roles in lethal and incurable castration-resistant prostate cancer (CRPC). EPI-002 is a novel small molecule that specifically targets the AR N-terminal domain (NTD), while conventional therapies target the ligand-binding domain (LBD). Our previous work suggests that EPI-002 may have clinical potential to treat CRPC. Here, the objective was to evaluate EPI-002 against several clinically relevant conditions such as elevated expression of AR co-activators, variable lengths of the poly-glutamine tract (CAG-repeats) within AR NTD, and constitutively active AR splice variants lacking the LBD.
Methods:
To evaluate the effect of EPI-002 on AR transcriptional activity against overexpressed co-activators such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells transfected with an AR-driven reporter and various amounts of the co-activators. AR-negative COS1 cells were employed for reporter assays to examine if the length of CAG-repeats (varying from 0 to 49) affects EPI-002 inhibition. The effect of EPI-002 on constitutively active AR splice variants was studied in LNCaP95 cells, which express endogenous AR-V7 variant. The expression of several genes regulated by AR-V7 was analyzed by QPCR in LNCaP95 cells treated with antiandrogen enzalutamide or EPI-002. The proliferation of LNCaP95 cells treated with EPI-002 was measured using BrdU incorporation. The efficacy of EPI-002 on LNCaP95 xenografts was studied in castrated male mice by oral delivery and compared to control and enzalutamide.
Results:
EPI-002 effectively inhibited AR transcriptional activity in spite of overexpressed co-activators SRC1, SRC2, SRC3, or p300. The variable lengths of CAG-repeats within the NTD had no effect on the inhibition of AR by EPI-002. In LNCaP95 cells, EPI-002 significantly blocked the transcriptional activity of AR-V7 indicated by decreased levels of mRNA of AR-V7 regulated genes such as UBE2C. In contrast, enzalutamide had no effect on expression of these genes. EPI-002 significantly inhibited the androgen-independent and antiandrogen-resistant proliferation of LNCaP95 cells. In castrated male mice, EPI-002 attenuated the growth of LNCaP95 xenografts, whereas enzalutamide had no significant effect. By the end of the 28-day study, animals treated with EPI-002 had xenografts that were half of the size of those from the control arm.
Conclusions:
AR NTD inhibitor EPI-002 was effective against several clinically relevant conditions, including overexpressed co-activators, variable lengths of CAG-repeats, and constitutively active AR-V7. These findings support EPI-002 as a promising therapeutic agent to treat CRPC, particularly against castration-resistant tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting therapies.
Citation Format: Yu Chi (Kevin) Yang, Nasrin (Rina) Mawji, Jean Wang, Marianne Sadar. Preclinical evaluation of novel androgen receptor N-terminal domain inhibitor EPI-002 for the treatment of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 610. doi:10.1158/1538-7445.AM2014-610