Abstract IA26: Dual functions of PARP1 in prostate cancer: mechanisms and implications for therapeutic intervention

Abstract

Abstract 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. The function of PARP1 in DNA repair has been cultivated as a therapeutic target for tumors incurring alterations of specific DNA repair pathways. However, it is now clear that factors beyond DNA repair alterations play a role in the response to PARP1 inhibitors-- as noted in the TO-PARP trial, not all patients with DNA repair alterations responded to PARP1 inhibitors as single agents; conversely, a significant number tumors lacking BRCA1/2 or other DNA repair alterations show objective responses to PARP1 inhibitors in PCa and other cancers. PARP1 is known to harbor a second major cellular function on chromatin as a transcriptional co-regulator, capable of modulating chromatin structure and selected transcription factor activity. Notably, previous studies demonstrated that PARP1 regulates AR residence on chromatin, and downstream AR-dependent tumor progression. Recent unpublished studies to be discussed demonstrate that PARP1 activity is significantly enriched in lethal disease, and that a newly identified gene signature of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 function as single agents in advanced prostate cancer, manifest through both DNA repair and transcriptional regulatory functions. Citation Format: Karen E. Knudsen. Dual functions of PARP1 in prostate cancer: mechanisms and implications for therapeutic intervention [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA26.