PROJECT SUMMARY/ABSTRACT The overall purpose of the Preclinical Models Core is to facilitate the accomplishment of the translational research goals and objectives of the SPORE by providing investigators with a biobank of state-of-the-art patient-derived and genetically engineered mouse models (GEMMs) of prostate cancer. These models include 23 patient-derived organoid (PDO) lines and 14 patient-derived xenograft (PDX) lines, as well as GEMMs of genetic alterations studied in the SPORE projects and organoids derived from these models. In addition, the Preclinical Models Core will provide assistance in the design and generation of transgenic and knockout/knockin mouse strains and will serve as a centralized repository for these mouse strains and materials of common interest, such as dissected tissues, DNA, RNA, and protein extracts from these strains. The Preclinical Models Core will generate, characterize, and maintain clinically and molecularly annotated PDOs and PDXs for use by SPORE investigators; generate and provide a repository of GEMMs and murine engineered prostate organoid models; and provide histopathologic analyses and design preclinical trials. The Preclinical Models Core will collaborate with RP-1 to use unique PDOs with mutations in homologous recombination genes as well as mouse organoids with BRCA2 deletion for validation studies of determinants of PARP inhibitor sensitivity; with RP-2 to provide genetically defined models for preclinical trials to evaluate targeting of the NRG1-HER2/3-PI3K pathway and to provide GEMMs to study the prostate microenvironment; and with RP-3 to provide PDX, PDO, and genetically engineered mouse–derived organoid models of lineage plasticity.