PROJECT SUMMARY / ABSTRACT – OVERALL Prostate cancer is the second leading cause of cancer deaths of men in the United States and places a significant health burden on society. The overarching goal of the UCSF Prostate Cancer SPORE is to address this burden by reducing the morbidity and mortality associated with prostate cancer, through leveraging a deep understanding of the disease to translate biological findings into clinical impact. The SPORE team will approach this mission with transdisciplinary research that is highly collaborative and translational, through four specific aims: A) Investigate molecular drivers of aggressive prostate cancer; B) Develop biomarkers to guide treatment of patients with advanced prostate cancer; C) Target therapeutic resistance in metastatic castration resistant prostate cancer (mCRPC), which is the lethal manifestation of advanced disease; and D) Accelerate translational research across the spectrum of prostate cancer. To address these aims, the UCSF Prostate SPORE proposes three scientific projects, each investigating aggressive prostate cancer from a mechanistic, biomarker, and therapeutic perspective: Project 1: Combination immunotherapy with radioligand therapy for metastatic prostate cancer Project 2: Investigating Clinical and Biological Implications of a Novel Hypermethylated Subtype of mCRPC Project 3: Deciphering the Role of the Translational Oncogenic Program in Prostate Cancer These proposed studies will be aided by horizontal collaborations with other Prostate SPORES, NCI initiatives, and molecular diagnostics companies, as well as vertical collaborations with the National Clinical Trials Network (NCTN), DOD Prostate Cancer Clinical Trials Consortium (PCCTC), and pharmaceutical companies, among other organizations. Additionally, these projects will be complemented by strong, ongoing institutional commitments of money and space, well-resourced Career Enhancement and Developmental Research Programs, and three cores: Administration, Biostatistics/Bioinformatics, and Pathology/Tissue. The infrastructure outlined under this SPORE application is designed to encourage and promote translation of innovative, impactful ideas by supporting promising new projects, providing access to critical resources for bench-to-bedside transitions, sponsoring interdisciplinary collaborations, and providing an effective framework for mentoring/nurturing the next generation of translational scientists. By bringing together a diverse and multi- disciplinary group of investigators, this Prostate Cancer SPORE will accelerate highly impactful translational research with the potential to significantly improve clinical outcomes for men with aggressive prostate cancer.

PROJECT NARRATIVE – OVERALL The UCSF Prostate Cancer SPORE seeks to reduce the morbidity and mortality associated with prostate cancer by leveraging a deep understanding of the disease to translate biological findings into clinical impact. In this SPORE application, three translational projects focus on developing novel biomarkers and highly effective therapies for patients with aggressive prostate cancer. These projects are highly collaborative with respect to the multidisciplinary nature and expertise of the Co-Leaders.