Grappling with the androgen receptor: a new approach for treating advanced prostate cancer

Abstract

In this issue of Cancer Cell, Andersen et al. report on a small molecule that interacts with and blocks transactivation of the androgen receptor amino-terminal domain. This agent can overcome the shortcomings of clinically used antiandrogens, an important advance in the development of effective therapy for advanced prostate cancer.

Fig. 1

Potential of EPI-001 to inhibit specific aberrant androgen receptor (AR) transactivation activities that contribute to castrate-resistant prostate cancer (CRPC). (A) On the basis of its interaction with the AF-1 region of the AR amino-terminal domain (NTD), EPI-001 would not be expected to reduce the selection pressure for AR amplification and/or mutations in the AR NTD that are associated with CRPC. However, because EPI-001 does not interact with the ligand-binding domain (LBD) or reduce ligand binding, it is unlikely that treatment would impose selection for gain-of-function LBD mutations that allow for AR-mediated activities in the presence of reduced or altered ligands. (B) EPI-001 can block forskolin (FSK)- or IL-6-mediated ligand-independent AR transactivation activities. (C) EPI-001 can inhibit a constitutively active AR deletion mutant that lacks the LBD. P, possible AR phosphorylation sites; filled rectangles, proteins that interact with AR to promote FSK- or IL-6–mediated ligand-independent AR transactivation; DBD, DNA-binding domain; AF-1, activation function-1; AF-2, activation function-2. AR protein domains are not drawn to scale.