Towards characterization of Epigenetic targets in Prostate Cancer

Project Summary: Prostate cancer (PCa) affects nearly 250,000 men in the United States annually, making it the second leading cause of cancer-related deaths in men, with over 30,000 fatalities each year, mainly due to metastatic castration-resistant prostate cancer (mCRPC). The androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. However, AR gets hijacked upon transformation, and the cancer cells become dependent on its activity. This dependency makes androgen/AR-targeted therapies common after initial treatments like surgery or radiation. However, the disease often returns through various mechanisms that restore AR-signaling, driving cancer progression. Despite advancements in antiandrogen therapies, 20-40% of mCRPC patients show resistance to drugs like abiraterone and enzalutamide, and many others develop resistance over time. A major challenge in treating advanced PCa is its reliance on AR-driven oncogenic transcriptional program, which involves multiple cofactors and chromatin proteins. Our long-term goal is to identify, characterize, and therapeutically target these cofactors and chromatin-associated proteins in the context of AR signaling in prostate cancer. We previously demonstrated that NSD2 overexpression is associated with PCa progression. NSD2 (also named MMSET and WHSC1), a histone lysine methyltransferase that catalyzes H3K36me2, is also implicated in the pathogenesis of multiple myeloma and other hematological malignancies. Here, we identify NSD2 as a critical subunit of AR enhanceosome (protein complex that assembles at enhancer regions) required for the oncogenic AR transcriptional program. Our preliminary work indicates that the NSD2 interacts with AR through its HMG-box domain and requires NSD2 catalytic activity to form the functional AR enhanceosome. In Aim 1, we propose to gain deeper molecular mechanistic insights into how NSD2 influences the chromatin landscape to facilitate the assembly of the AR enhanceosome complex and enhance long-range enhancer-promoter looping for a hyperactive AR transcriptional program in PCa cells. In Aim 2, we will evaluate the therapeutic potential of a novel first-in-class small molecule inhibitor of NSD2, which also inhibits its paralog NSD1, in AR-driven prostate cancer in vivo. This includes assessing the on-target activity and anti-tumor effects of the compound in various prostate cancer models, including naïve and Enza-refractory CRPC, primary explant, and organoid models. Together, these studies will provide critical new insights into how epigenetic modifiers regulate oncogenic transcription factors to drive cancer progression.