Abstract B059: Understanding the role of poly (ADP-ribose) polymerase 1 (PARP-1) activity in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the most diagnosed cancer in men in the United States. African American men have two times higher incidence rate and death rate from PCa than European American men. In PCa, the androgen receptor (AR) acts as a pro-oncogenic transcription factor. Androgen deprivation therapy (ADT) and AR antagonists are the current standard of care for advanced PCa. Late stage of disease is recognized as metastatic castrate resistant prostate cancer (mCRPC) due to adaptive resistance to ADT. mCRPC remains universally fatal with no durable therapeutic options. Poly (ADP-ribose) polymerase 1 (PARP-1) has been identified as a driver of cancer cell survival through the recruitment of DNA-damage-repair enzymes and regulation of oncogenic transcription factors, such as AR, in PCa. PARP-1 enzymatic activity is elevated in mCRPC patient tumors as compared to primary tumors. Although increased PARP activity in these tumors has been shown to be a driver of cancer cell survival, the mechanisms and consequences of elevated PARP activity in PCa remains an active research program in our lab, especially regarding PARP-responsive transcriptional networks. PARP inhibitors (PARPi) have been approved for use in mCRPC with alterations in homologous recombination (HR) genes. The experiments below are designed to better understand the mechanisms by which PARP enzymes may transcriptionally regulate and promote pro-tumorigenic functions. Five different PARP inhibitors were analyzed in a CRPC cell line model to assess their relative potencies and develop IC50 values. A cell growth assay using trypan blue exclusion was used to compare the effectiveness of this IC50 value in regular growth conditions as it compares to steroid depleted growth conditions used to mimic ADT. Immunoblot analyses show that there is differential impact on PARP activity (PARylation) in response to the PARPi tested at the respective IC50 concentrations. It will be imperative to better understand how PARP-1 manipulation regulates gene expression. Tissue microarray (TMA) data was analyzed to assess the level of PARP-1, PAR & gH2AX levels in tissue derived from African American versus European American patients. Although not statistically significant, higher PARylation levels were present in African American TMAs compared to European American prostate tumors. It is essential to obtain TMAs representing a more diverse patient demographic to further assess this difference in PARylation levels As well as TMA data, Patient-Derived Explants (PDEs) from patients with different racial backgrounds were assessed for differential impact of PARPi based on race. Collectively, these studies and future studies for this project will further establish the impact of PARP on PCa gene expression programs and provide resources for future studies exploring PARP in PCa. Further, they may help elucidate mechanisms to address PCa racial disparities. Citation Format: Moriah Cunningham, Latese Evans, Salome Tchotorlishvili, Jasibel Vasquez Gonzalez, Candice Bizzaro, Matthew Schiewer. Understanding the role of poly (ADP-ribose) polymerase 1 (PARP-1) activity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B059.