Overall Project Summary/Abstract Prostate cancer has become the most frequently diagnosed cancer in men in the United States (US) and a major cause of cancer morbidity and mortality, with 33,000 American men (~90 every day) dying annually from the disease. Considerable progress over the last decade resulted in the approval of multiple new hormonal and cytotoxic therapies, each producing modest improvement in survival. Yet, despite a broad palette of therapeutic options and the emerging promise of immunotherapy, the cure of metastatic prostate cancer has remained elusive. However, over the past two decades, dedicated prostate cancer research, accomplished by Johns Hopkins Prostate Cancer Program investigators and other researchers, led to a remarkable accumulation of knowledge about the molecular mechanisms by which human prostate cancers arise and progress. These studies identified adaptive autoregulation of androgen receptor activity, mutations and alterations in DNA-repair pathways and an immunosuppressive microenvironment as fundamental characteristics of prostate cancer producing resistance to hormonal, DNA-targeted and immune based therapies and allowing for progression that eventually threatens life. To make significant advancement in the treatment of prostate cancer, the goal of this new Prostate SPORE application is to translate new insights about the role played by adaptive changes in the hormonal axis, DNA-repair and the immune system in the pathobiology of prostate cancer into new hypotheses tested in clinical trials. The transcendent overall objective of the Johns Hopkins Prostate Cancer SPORE is to reduce prostate cancer mortality via the focused pursuit of translational research in prostate cancer.

Overall Project Narrative This SPORE is dedicated to improving outcomes from prostate cancer, which affects 1 in 8 men in the United States, by delivering three new approaches to prostate cancer treatment. Over the planned 5 years of funding, three new combinatorial treatment strategies will be evaluated in clinical trials and in correlative laboratory-based studies to assess their effectiveness in men with prostate cancer.