PROJECT SUMMARY – OVERALL The Dana-Farber/Harvard Cancer Center (DF/HCC) Prostate SPORE seeks to improve the understanding and treatment of prostate cancer using a highly translational approach. The application consists of three Projects, three Cores, a Developmental Research Program and a Career Enhancement Program. The SPORE infrastructure will facilitate interactions and collaboration within our thriving community of basic, clinical, and population science researchers dedicated to prostate cancer research. Each project addresses a fundamental challenge that contributes to prostate cancer morbidity and mortality. Project 1 leverages tumor specimens from patients with high-risk prostate cancer treated with neoadjuvant therapies to understand how tumors respond and resist acute potent androgen receptor blockade and to develop novel strategies to improve cure rates and combat resistance. Project 2 will develop innovative strategies to target the epigenome in later stages of advanced castration resistant prostate cancer and will develop a first-in-field clinical trial focused on co-targeting EZH2 and PARP. Project 3 delves deep into biomarkers in localized prostate cancer, leveraging innovations in computation and biologically-guided deep learning, to deliver on precision cancer medicine in this disease state. The ability to understand why some localized prostate cancers are phenotypically aggressive and predict which localized prostate cancers will behave in this manner addresses a large clinical unmet need. Each of these projects combines elegant preclinical work with innovative clinical studies led by DF/HCC investigators. Core A, the Administrative Core, will be the center for scientific, fiscal and administrative oversight. It will lead efforts in planning and communication, and also house the Patient Advocacy Committee. Core A will ensure that the DF/HCC infrastructure supports the SPORE clinical and translational research efforts. Core B, the Biostatistics and Computational Biology core, will provide specialized expertise in biostatistics and the management of genomic and other next generation sequencing data and data sharing. Core C, the Biospecimen and Pathology Core, will maintain tissue/blood repositories for the SPORE projects as well as other investigators within the prostate cancer program. It will provide critical expertise and pathology services including next generation molecular assays and will help facilitate the use of fresh tumor specimens including rapid autopsies for patient derived model development to accelerate translational investigation. The Developmental Research and Career Enhancement Programs will identify and fund innovative projects that address basic, translational, and clinical research questions and unmet needs in prostate cancer and will support early career and new prostate cancer investigators. These programs will actively recruit and retain researchers from diverse backgrounds to foster cutting-edge and impac...