Cross talk of the androgen receptor and DNA damage pathways: <em>molecular and translational prostate cancer relevance</em> — ASN Events
  1. Schedule
  2. ESA/AWE Basic Science Symposium – Reproductive Cancers
  3. Cross talk of the androgen receptor and DNA damage pathways: molecular and translational prostate cancer relevance

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.

  1. Knudsen KE, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res. 2009;15(15):4792-8.
  2. Knudsen KE, Penning TM. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab. 2010;21(5):315-24. PMCID: 2862880.
  3. Kraus WL. Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Curr Opin Cell Biol. 2008;20(3):294-302. PMCID: 2518631.
  4. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2011 ;10(4):293-301. PMCID: 2910902.
  5. Yap TA, Sandhu SK, Carden CP, de Bono JS. Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin. 2011;61(1):31-49.
  6. Frizzell KM, Kraus WL. PARP inhibitors and the treatment of breast cancer: beyond BRCA1/2? Breast Cancer Res. 2009;11(6):111. PMCID: 2815546.
  7. Frizzell KM, Gamble MJ, Berrocal JG, Zhang T, Krishnakumar R, Cen Y, et al. Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cells. J Biol Chem. 2009;284(49):33926-38. PMCID: 2797163.
  8. Krishnakumar R, Kraus WL. PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. Mol Cell. 2011 ;39(5):736-49. PMCID: 2939044.