Since inception in 1995, the University of Michigan (U-M) Prostate SPORE has endeavored to tap the vast intellectual and physical resources of the U-M community to decrease the morbidity and mortality of prostate cancer (PCa). In this renewal application, U-M joins forces with Karmanos Cancer Institute (KCI) to propose a “Michigan Prostate SPORE” leveraging our institutions' respective areas of strength. KCI has a non-overlapping patient population as U-M, which includes an underserved population. The Michigan Prostate SPORE supports an interactive group of basic and clinical investigators in a translational research program that has led to major discoveries in the diagnosis, prevention, and treatment of PCa. Successful translation of discoveries in the most recent grant period include: 1) The ETS gene fusions (which were discovered by this SPORE program) have been established as a urine test for the early detection of PCa (JAMA Oncology 2017 3:1085) and have been therapeutically targeted with peptidomimetic inhibitors (Cancer Cell 2017 31:844). 2) Our SPORE program played a significant role in defining the clinically actionable landscape of metastatic castration-resistant prostate cancer (mCRPC) (Cell 2015, 162:454) which led to the discovery that upwards of 20-25% of mCRPC harbor defects in DNA repair genes. As part of the TO-PARP study, we showed that mCRPC patients with DNA repair defects preferentially respond to PARP inhibitors (NEJM 2015, 373:1697). 3) Established that BET bromodomain inhibitors may be useful in the treatment of advanced PCa by blocking oncogenic transcription factor activity (Nature 2014, 510:278). 4) Several PCa-associated long non-coding RNAs, including PCAT1, Schlap1 (Nature Genetics 2013 45:1392), and ARlnc1 (Nature Genetics 2018, 50:814) were discovered and characterized. These bench-to-bedside applications were aided by horizontal collaborations with the University of Washington, Dana Farber, Memorial Sloan-Kettering, and Weill-Cornell Prostate SPOREs as well as the EDRN and vertical collaborations with SWOG and biotech companies. This application consists of four projects: Project 1: Targeting mCRPC Patients with Biallelic Loss of CDK12; Project 2: Integrating a Novel MiPS-Based Next- Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk PCa; Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for mCRPC; Project 4: Targeting Autophagy in the Treatment of mCRPC. These projects are complemented by strong, ongoing institutional commitments of money and space, successful Career Development and Developmental Research Programs, and three cores: Administration, Biostatistics/Bioinformatics, and Biospecimen/Pathology. The Michigan Prostate SPORE continues to place premiums on rigorous scientific review of its translational research programs, pairing of basic and clinical investigators, drawing on expertise of scientists from within and from outside the PCa field, and uti...