Funded by the Stewart J. Rahr Foundation PCF Challenge Award:
co-funded by The Prostate Cancer Foundation and
the 2016 V Foundation Wine Celebration Fund a Need
Nearly all patients with metastatic castration resistant prostate cancer (mCRPC) develop resistance to androgen targeting agents and ultimately succumb to their disease. Recent discoveries by our group and others have demonstrated that a significant proportion of these patients harbor somatic or germline genomic defects in DNA repair defects, and targeting this genomically defined subset with therapies affecting this pathway may impact patient care. The goal of this project is to definitively characterize the genomic and functional landscape of DNA repair defects in mCRPC, clinically test the hypothesis that tumors harboring DNA repair defects preferentially benefit from immune checkpoint blockade, and explore innovative strategies to augment the efficacy of these agents through genomic and preclinical approaches. The project described herein is the first to comprehensively bridge the DNA repair and immuno-oncology fields to directly impact patients with advanced prostate cancer. We propose an integrated strategy that leverages advances in clinical genomics, trial design, and preclinical modeling methodology pioneered by our team. Furthermore, our proposal will be the first to specifically enable immune checkpoint blockade treatment strategies for mCRPC. In summary, this project will catalyze our understanding of how DNA repair defects impact advanced prostate cancer, and how deep knowledge about these events may enable clinical development of a transformative new class of immunotherapies that are greatly needed for advanced prostate cancer patients.