Abstract 1516: Androgen-repressed and androgen-induced genes: challenging the traditional dogma of prostate cancer therapy
Authors: Caley Daniel P. , Mawji Nasrin R. , Sadar Marianne 
Published: July 2017

Background: Benign and malignant prostate tissues are dependent upon the activity of androgen receptor (AR). The primary function of full-length AR is as a ligand activated transcription factor to increase or repress gene expression. Many androgen-repressed genes regulate the cell cycle and proliferation. With castration, the main therapeutic approach for advanced prostate cancer (PC), these genes are believed to play a role in the initial clinical response. Current approved therapies for advanced PC and castration-resistant PC (CRPC), target the AR C-terminal ligand-binding domain (LBD), such as antiandrogens. Recent antagonists of the AR N-terminal domain (NTD) have been described with EPI-506, the prodrug of EPI-002, now in Phase 1 clinical trials. EPI-002 binds tau-5 in activation function-1 (AF-1) of the NTD that is essential for AR transcriptional activity. As expected with an AF-1 antagonist, EPI-002 is an excellent inhibitor of androgen-induced gene expression and at blocking the transcriptional activities of truncated AR splice variants lacking LBD, such as AR-V7. EPI-002 blocks expression of genes regulated by truncated AR-V7 such as UBE2C while antiandrogens have no effect. Here we reveal that the major difference in gene expression regulated by full-length AR between EPI-002 and antiandrogens is their abilities to de-repress genes that are turned off by androgen.

Methods: The androgen sensitive human prostate cancer cell line LNCaP, which expresses full-length AR, was treated with antiandrogens (bicalutamide [BIC] and enzalutamide [ENZA]), EPI-002 and a control vehicle, with and without androgen. Gene expression was analysed using Affymetrix microarrays. Bioinformatical analysis was completed and a selection of androgen-repressed genes that were de-repressed with antiandrogens and/or EPI-002, were selected for validation using qRT-PCR.

Results: EPI-002 de-repressed known androgen-repressed genes including SPLTLC3, ST7, PSAT1, TMEM140 and TNFRSF21. EPI-002 was as effective or better than BIC or ENZA in de-repressing a subset of androgen-repressed genes. Importantly, EPI-002 failed to de-repress expression of many androgen-repressed genes that antiandrogens de-repressed, such as SLITRK3, GPR63 and DAB1.

Conclusions: EPI binds AR NTD which blocks the transcriptional activities of full-length AR and truncated AR splice variants. EPI-002 was excellent at inhibiting androgen-induced genes. However, EPI did not broadly de-repress expression of genes turned off by androgen when compared to antiandrogens. Such differences between EPI-002, a tau-5/NTD antagonist, and C-terminal LBD antiandrogens probably reflect the complexities of the mechanisms of repression of gene expression that may involve different domains of AR.

Citation Format: Daniel P. Caley, Nasrin R. Mawji, Marianne Sadar. Androgen-repressed and androgen-induced genes: challenging the traditional dogma of prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1516. doi:10.1158/1538-7445.AM2017-1516