Abstract While over 90% of patients with metastatic prostate cancer respond to systemic therapies that block androgen receptor signaling, nearly all of these patients will eventually relapse and die due to development of acquired therapy resistance. Thus, strategies to prevent acquired therapy resistance are needed. We have identified a rare molecular subtype of prostate cancer with isocitrate dehydrogenase 1 (IDH1) mutation that fails to acquire resistance to therapy. This exploratory proposal will investigate mechanisms by which IDH1-mutant prostate cancer fails to acquire resistance to therapy with a goal to identify novel therapeutic targets to prevent resistance. Molecular consequences of IDH1 mutation in cancer have been previously studied in AML and glioma where it has been shown that IDH1 mutation leads to accumulation of R-2HG, inhibition of 2OG dioxygenases, increased DNA and histone methylation, and marked alteration of epigenetic regulation of gene transcription. However, AML and glioma are different from most solid tumors including prostate cancer because they do not metastasize and have unique treatment paradigms. We will test the hypothesis that IDH1-mutant prostate cancer is restricted in epigenetic control of gene transcription, rendering it less able to adapt to stress such as therapy, and that inhibition of a 2OG-dioxygenase(s) enhances response to therapy. In Aim 1 we will study the largest cohort of patients with IDH1-mutant prostate cancer to date to describe clinical, genomic, and transcriptomic features of this disease. Aim 2 is to develop a transgenic murine model of IDH1-mt prostate cancer to study mechanisms of therapy resistance and sensitivity in vivo. In Aim 3, we will perform a targeted CRISPR-KO screen to identify 2OG-dioxygenases that upon deletion increase DNA methylation and therapy sensitivity in prostate cancer. Together, these aims will provide insight into molecular consequences of IDH1 mutation in prostate cancer and may identify novel drug targets to disable epigenetic plasticity required for acquired resistance to therapy.