Abstract C8: Targeting the DNA-damage repair and transcriptional regulatory functions of PARP1 therapeutically in prostate cancer

Poly (ADP-ribose) polymerase 1 (PARP1) is an abundant nuclear enzyme that modifies substrates by poly (ADP-ribose)-ylation. While PARP1 has a well-described role in repair of DNA damage (especially as associated with base excision repair), substantive evidence suggests that PARP1 has additional functions in transcriptional control. The transcriptional regulatory functions of PARP1 are multi-fold, do not universally require enzymatic activity, and are manifest through divergent functions including: enhancer binding, association with insulators, modulation of chromatin structure, and/or direct transcription factor regulation. Recent pre-clinical studies and pre-clinical trials have illuminated the importance of PARP1 in human cancers, in that enzymatic inhibitors of PARP1 create synthetic lethal events in tumors deficient in PTEN or BRCA1/2, and/or sensitize to DNA damaging agents. Given the poor response of prostatic adenocarcinomas (PCa) to DNA damaging agents, initial studies were performed to assess the impact of PARP1 inhibitors on radiation and chemotherapy responses. Consistent with studies in breast cancer, PARP1 inhibition sensitizes cell model systems of multiple stages of PCa to DNA damaging agents. However, an unexpected finding was noted in that PARP1 inhibition exhibited a single agent effect in cells positive for the androgen receptor (AR). These findings were consistent in both cells responsive to androgen deprivation therapy (ADT), which is the first line of intervention for disseminated disease, as well as therapy-resistant cells. Mechanistic exploration revealed that PARP1 is a critical effector of AR activity, and is recruited to sites of AR function upon receptor activation. Suppression of PARP1 activity significantly impaired transcriptional activation of endogenous AR target genes, including PSA, which is used clinically to monitor prostate cancer growth and progression. Genetic deletion of PARP1 similarly compromised AR activity, and restoration of PARP1 functional domain mutants into this model system allowed for confirmation of the posit that PARP1 catalytic activity is essential for supporting AR activity. Additionally, inhibiting PARP1 catalytic activity suppressed PCa xenograft tumor growth in vivo. Finally, PARP1 inhibition as decreased the proliferative capacity of primary human tumors in a novel explant model system. Collectively, these studies identify PARP1 as a key mediator of AR activity that could be targeted in advanced disease to both suppress AR signaling and improve response to therapeutic DNA damaging agents. As such, multiple clinical trials are currently being written that are supported by the data that will be presented herein. Citation Format: Matthew J. Schiewer, Adam P. Dicker, Jonathan R. Brody, John M. Pascal, Lisa M. Butler, Wayne D. Tilley, Felix Y. Feng, Karen E. Knudsen, Jonathan F. Goodwin, J Chad Brenner, Michael A. Augello, Fengzhi Liu, Jamie L. Planck, Randy S. Schrecengost, Arul M. Chinnaiyan, Ganesh V. Raj. Targeting the DNA-damage repair and transcriptional regulatory functions of PARP1 therapeutically in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C8.