Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2012

Cross talk of the androgen receptor and DNA damage pathways: molecular and translational prostate cancer relevance (#164)

Matthew J Schiewer 1 , Jonathan F Goodwin 1 , J. Chad Brenner 2 , Michael A Augello 1 , Fengzhi Liu 3 , Jamie L Planck 4 , Randy S Schrecengost 1 , Felix Y Feng 5 , Arul M Chinnaiyan 6 , Adam P Dicker 7 , Jonathan R Brody 3 , John M Pascal 4 , Karen Knudsen 8
  1. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University , 233 S 10th St Philadelphia, PA 19107, USA
  2. Department of Pathology, Program in Cellular and Molecular Biology, Michigan Center for Translational Pathology, University of Michigan, 1400 E Medical Drive, 5316 CCGC Ann Arbor, MI 48109, USA
  3. Department of Surgery, Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St Philadelphia, PA 19107, USA
  4. Department of Biochemistry, Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St Philadelphia, PA 19107, USA
  5. Department of Radiation Oncology, Michigan Center for Translational Pathology, omprehensive Cancer Center, University of Michigan, 1400 E Medical Drive, 5316 CCGC Ann Arbor, MI 48109, USA
  6. Michigan Center for Translational Pathology, Department of Pathology, Program in Cellular and Molecular Biology, Department of Radiation Oncology, Howard Hughes Medical Institute, Department of Urology, Comprehensive Cancer Center, University of Michigan, 1400 E Medical Drive, 5316 CCGC Ann Arbor, MI 48109, USA
  7. Departments of Cancer Biology & Radiation Oncology , Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St Philadelphia, PA 19107, USA
  8. Departments of Cancer Biology, Urology & Radiation, Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St Philadelphia, PA 19107, USA

Prostate cancers (PCa) are exquisitely dependent on the action of the androgen receptor (AR) for cell survival and proliferation, and there is a significant need to develop new means for targeting recurrent AR activity in both locally advanced and castration-resistant PCa(1, 2). PARP1 (Poly ADP-ribose polymerase 1) is an enzyme that modifies a subset of nuclear proteins by poly (ADP-ribose)-ylation, and is known to play a critical role in base excision repair(3).  This function of PARP1 has been cultivated as a therapeutic target for tumors tumors that harbor alterations of specific DNA repair pathways(4, 5). Multiple enzymatic inhibitors of PARP1 function are in clinical trial; while little dose limiting toxicity has been observed, suppressing PARP1-mediated DNA damage repair in BRCA1/2 deficient tumors leads to synthetic lethality and heightened clinical response to chemotherapy. Recently, it has been revealed that PARP1 has a second major cellular function on chromatin as a transcriptional coregulator, capable of modulating chromatin structure and selected transcription factor activity(6-8).

New observations in our laboratory point toward PARP1 inhibitors as a means to simultaneously dampen AR activity and sensitize PCa cells to genotoxic insult. This premise is based on three major arms of investigation.  First, abrogation of PARP1 activity results in sensitization of both androgen deprivation-therapy (ADT) naïve and castration-resistant PCa cells to ionizing radiation, thus indicating that PARP1 activity plays a significant role in the cellular response to radiotherapy.  Second, PARP1 activity was found to be increased as a function of tumor progression in model systems of human disease, suggesting that gain of PARP1 activity may promote resistance to combined ADT and radiotherapy.  Third, robust molecular analyses indicate that PARP1 is recruited to sites of AR activity on chromatin, and therein serves as a requisite cofactor for AR activity.  The dependence of AR on PARP1 activity is conserved in cells that failed hormone therapy, thus indicating that the requirement for PARP1 is maintained or enhanced during the process of tumor progression. Together, these data strongly support a model wherein the dual functions of PARP1 in controlling AR activity and the response to radiotherapy can be leveraged to improve treatment of locally advanced prostate cancer.

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