Endocrine Abstracts

Prostatic adenocarcinoma (PCa) is the 2nd leading cause of cancer death in US men. Organ-confined PCa can be effectively managed, but there is no durable treatment for advanced disease. Advanced PCa is treated through androgen deprivation therapy, often coupled with direct AR antagonists, as PCa is exquisitely dependent on androgen receptor (AR) activity for survival. Furthermore, recent studies identified AR as a major effector of DNA repair, manifest through the ability of the receptor to regulate DNAPK expression and activity. While AR directed therapeutics effectively suppress the pro-proliferative, pro-survival, and pro-DNA repair functions of AR and result in tumor remission, relapse is common. Recurrent disease arises largely due to resurgent AR activity with 2–3 years, and there is no cure for this castration-resistant phase (CRPC, castration-resistant PCa). Thus, there is a significant need to develop new means for targeting recurrent AR activity or develop adjuvant therapies in advanced PCa.

Emerging data from our laboratory and others strongly support the concept that AR regulates DNA repair pathway, and that alterations in DNA damage repair (DDR) pathways are more common than previously thought in sporadic PCa, thus uncovering new, potentially more effective means of therapeutic intervention. New studies to be discussed will address underlying mechanisms of action with regard to the pathway, and identify clinically actionable ramifications of AR-DNA repair dysfunction. Major concepts to be considered include new discoveries regarding PARP1 function and activity in lethal disease, and that a newly identified gene signature of PARP1-regulated networks is associated with poor outcome. Further, mechanistic investigation revealed new insight into the means by which PARP1 inhibitors likely act as single agents in advanced prostate cancer, manifest through both DNA repair and transcriptional regulatory functions. Findings to be discussed strongly support a model wherein selected DDR pathways can be developed as therapeutic targets in concert with AR-targeting strategies to tailor treatment for prostate cancer and improve outcome for advanced disease.

DOI: 10.1530/endoabs.54.PL3