Outsmarting androgen receptor: creative approaches for targeting aberrant androgen signaling in advanced prostate cancer

Abstract

Prostatic adenocarcinomas are reliant on androgen receptor (AR) activity for survival and progression. Therefore, first-line therapeutic intervention for disseminated disease entails the use of AR-directed therapeutics, achieved through androgen deprivation and direct AR antagonists. While initially effective, recurrent, 'castrate-resistant' prostate cancers arise, for which there is no durable means of treatment. An abundance of clinical study and preclinical modeling has led to the revelation that restored AR activity is a major driver of therapeutic failure and castrate-resistant prostate cancer development. The mechanisms underpinning AR reactivation have been identified, providing the foundation for a new era of drug discovery and rapid translation into the clinic. As will be reviewed in this article, these creative new ways of suppressing AR show early promise.

Figure 1. Mechanisms of androgen receptor reactivation in the transition to castration-resistant prostate cancer

As discussed, tumors evade hormone therapy through restoring AR activity, which can be achieved through multiple mechanisms. Agents designed to target hormone therapy-naive and recurrent AR activity are shown in red. AC: Acetylation; AR: Androgen receptor; CoACT: Coactivator; CoR: Corepressor; CRPC: Castration-resistant prostate cancer; DHT: Dihydrotestosterone; GF: Growth factor; GnRH: Gonadotropin-releasing hormone; HSP: Heat-shock protein; P: Phosphorylation; PSA: Prostate-specific antigen; SNARE: Soluble N-ethylmaleimide-sensitive factor attachment protein receptor; Sumo: Sumolyation; T: Testosterone.