Targeting Androgen Receptor Action for Prostate Cancer Treatment: Does the Post-Receptor Level Provide Novel Opportunities?

The standard of care for patients who suffer from non-organ confined prostate cancer (CaP) is androgen deprivation therapy (ADT). ADT exploits the reliance of CaP cells on androgen receptor (AR) signaling throughout CaP progression from androgen-stimulated (AS) to castration-recurrent (CR) disease. AR is a member of the nuclear receptor family of ligand-activated transcription factors. Ligand-activated AR relocates from the cytoplasm to the nucleus, where it binds to Androgen Response Elements (AREs) to regulate transcription of target genes that control CaP cell behavior and progression. Current forms of ADT interfere at 2 levels along the AR signaling axis. At the pre-receptor level, ADT limits the availability of ligand for AR, while at the receptor level, ADT interrupts AR-ligand interactions. Both forms of ADT induce remission, but are not curative and, because of extraprostatic actions, are associated with severe side effects. Here, the potential of interference with the molecular regulation of AR-dependent transcription and the action of AR target genes, at the post receptor level, as the foundation for the development of novel, more CaP- specific selective forms of ADT is explored.