Alternative approaches to prevent androgen action in prostate cancer: are we there yet?

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men in the U.S. Prostate cancer deaths are due to failure of androgen deprivation therapy (ADT). ADT is the standard of care for non-organ confined prostate cancer and inhibits action of androgen receptor (AR), which is necessary for the growth of prostate cancer. ADT blocks AR activity by preventing either production of its ligands or interaction between AR and its ligands. Following an initial remission, almost all patients experience prostate cancer recurrence during ADT. Remarkably, prostate cancer that reemerges remains dependent on AR. This recognition has led to the recent development of novel treatment strategies that focus on alternative means to target ligand production and availability for AR. These therapies induce remission and offer moderate survival benefits but none are curative while all are associated with significant side effects. We propose that an alternative tactic to achieve the beneficial effects of ADT could be explored by targeting a different step in the AR signaling cascade, namely the biological consequences of AR activation. Insights in molecular regulation of AR function and genome-wide AR action could be used to develop therapeutic interventions that focus on eliminating only distinct AR-dependent biological processes responsible for aggressive prostate cancer cell behavior. Such selective forms of ADT could be used alone or in combination with existing therapies to improve prostate cancer therapeutic outcome in a stage-specific and personalized manner.