Functional Characterization and Development of Therapeutic Paradigms for DNA Damage Repair (DDR)-deficient Lethal Prostate Cancer

Abstract A leading contributor to the significant mortality burden of prostate cancer, the second cause of cancer death among U.S. men, is the short-lived efficacy of androgen deprivation therapy (ADT), the mainstay of care for advanced and symptomatic disease. Increasingly alterations in DNA damage repair (DDR) genes, predominantly BRCA2, have been linked to ADT resistance and poor prognosis. We previously showed that deleterious alteration of BRCA2 is sufficient to induce ADT resistance in castration-sensitive prostate cancer (PC) cells. Our current proposal will investigate the molecular mechanism underlying BRCA2 loss/mutation- induced ADT resistance and progression to lethal prostate cancer. Using a panel of 107 DDR-associated genes from the PROREPAIR B cohort, we made the novel observation that ~82% of patients with mCRPC harbor alterations of one or more DDR genes. Herein, we aim to comprehensively investigate the role of DDR alterations (other than BRCA2) in the development of mCRPC and resistance to therapy. To do so, we will use CRISPR screening to prospectively investigate how the gain or loss-of-function alterations of DDR genes induce castration resistance. We have observed high expression levels of prostate-specific membrane antigen (PSMA) in response to the loss of BRCA2 and other DDR genes (e.g., ATM). Our second aim will investigate the impact of PSMA- targeted radiotherapy with [177Lu]-PSMA-617 and PARP inhibitor combination in BRCA2/DDR-deficient PC. Prostate cancer is predominantly resistant to immunotherapy. Since BRCA2-deficient cells also exhibit higher PSMA expression and are possibly immunogenic due to increased genomic instability, we will explore the effect of PSMA-targeted CAR T cells on BRCA2-deficient prostate cancer. Finally, as two PARP inhibitors (olaparib and rucaparib) have been approved to treat patients with DDR-deficient prostate cancer, we will investigate whether PARP inhibitors synergize with CAR T-cell therapy. For the first time, the proposed project will demonstrate the crucial importance of BRCA2/DDR alterations in prostate cancer biology and possibly lay the foundation for consideration of DDR alteration as the master driver of the transformation from indolent, localized prostate cancer to lethal mCRPC. We believe this work will lead to clinical trials that will establish new and effective treatments for this deadly disease.