PROJECT SUMMARY/ABSTRACT The Pacific Northwest (PNW) Prostate Cancer SPORE continuation grant represents a coordinated effort of four institutions with established programs and strengths in translational prostate cancer research including basic, clinical, and population sciences as well as career development: 1) the Fred Hutchinson Cancer Center (FHCC); 2) the University of Washington (UW) and its affiliated institutions; 3) the University of British Columbia and the Prostate Centre of Vancouver General Hospital (UBC); and 4) Oregon Health and Science University (OHSU). These Seattle-, British Columbia- and Portland-based institutions have large multidisciplinary teams of investigators and laboratories dedicated to prostate cancer research and a history of working closely together within this larger milieu. The respective teams of clinicians and researchers at these institutions bring considerable scientific depth, breadth, creativity, and vision required for confronting the most challenging problems blocking progress in our ultimate goal of reducing the morbidity and mortality associated with prostate cancer. This SPORE proposal enlarges the blueprint for a well-built, distinctive and coordinated translational prostate cancer research effort spanning the entire PNW. All participating institutions have made substantial commitments toward supporting the SPORE and its innovative, translational projects: 1) Molecular predictors of prostate cancer progression and mortality; 2) Understanding and targeting prostate cancer lineage plasticity; 3) Modulating androgen receptor signaling to enhance the efficacy of CAR T cell therapy for advanced prostate cancer; and 4) Clinical development of therapeutic strategies targeting DNA repair. We also propose three Cores to support these projects: 1) Leadership and administration; 2) Biospecimen and Pathology; and 3) Biostatistics and Bioinformatics. In addition, we propose a Developmental Research Program and a Career Enhancement Program that will substantially strengthen the translational goals of our prostate cancer research program and expand opportunities for engaging young as well as established investigators in our multidisciplinary environment.