Project Summary/Abstract Prostate cancer lethality is mainly due to metastasis, which occurs most frequently in bone and is associated with high morbidity. Despite recent progress, current treatments are not curative and therefore new therapeutic strategies are urgently needed. Given that both metastatic progression and therapeutic resistance occur in the context of a whole organism and are influenced by the tumor microenvironment, one significant challenge to our current understanding of metastatic progression is the paucity of models in which to study metastasis in its physiological context, and especially models that recapitulate the bone tropism of human prostate cancer. The overarching goal of this proposal is to understand how the molecular alterations present in lethal prostate cancers contribute to disease outcome and how to use this knowledge to develop more effective therapies. In particular, my preliminary data strongly suggests MYC as a driver of bone metastasis progression. Given that MYC has traditionally been hard to target therapeutically, this proposal will leverage unique mouse models of bone metastasis to address specific therapeutic vulnerabilities to target MYC signaling dependencies in prostate cancer. Specifically, in Aim 1 I will study small molecule inhibition of the ATAD2-bromodomain as a strategy to inhibit metastasis and therapy resistance. In Aim 2, I will use CRISPR screens to identify synthetic lethal vulnerabilities of prostate tumors with high MYC activation. In Aim 3, I will exploit CRISPR technology to somatically edit the genomes of mouse prostates in order to streamline the study of the phenotypic consequences of genetic alterations for prostate cancer progression. The career development plan outlined in this award leverages my training at Columbia University and an outstanding advisory committee into an innovative research plan to steer my career into specific precision medicine approaches for the treatment of prostate cancer bone metastasis. This proposal will provide the conceptual groundwork, preliminary data and experimental tools for a competitive R01 submission, thus launching my independent career. If successful, this award will provide proof-of-principle for a new class of targeted agents and uncover new therapeutic vulnerabilities in metastatic prostate cancer as occurs in vivo. This proposal will advance the field by potentially leading to novel clinically testable hypotheses that may guide clinical trials. Ultimately, these results will impact patient care by reducing the morbidity and mortality associated with metastatic prostate cancer.