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.

Keywords::

• abiraterone
• androgen receptor
• cell cycle
• hormone therapy
• prostatic adenocarcinoma
• retinoblastoma

Acknowledgements

The authors regret any omission of citations due to space constraints. They would also like to thank Michael Augello, Jonathan Goodwin, Matthew Schiewer and Randy Schrecengost for critical feedback and ongoing disussions, and Elizabeth Schade for assistance with illustrations.

Financial & competing interests disclosure

Karen E Knudsen is supported by grants CA09996 and ES16675 from the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.