Treatment-resistant neuroendocrine prostate cancer (NEPC) is a currently incurable, lethal subtype of prostate cancer that usually develops following prolonged hormonal therapy. The only treatment option for NEPC is a highly toxic chemotherapy, which provides only limited survival benefits. Therefore, more effective treatments are urgently needed to improve the management of NEPC. Our current research goal is to understand how NEPC develops and progresses and pave the road to develop new therapy for the disease treatment. Toward this end, our group has developed a panel of state-of-the-art pre-clinical models of NEPC, which are giving us unprecedented levels of accuracy in monitoring how NEPC progresses. Using these models and advanced gene expression analyses, we for the first time discovered a protein named SUV420H2 that plays an important role in NEPC development. We observed the increased expression of SUV420H2 in our models and clinical NEPC samples. Furthermore, we demonstrated the increased SUV420H2 expression can functionally promote NEPC development while its decreased expression inhibited NEPC cell growth. In the proposed study, we are aiming to further confirm the function of SUV420H2 in NEPC, understand how it causes NEPC development and aggressiveness and test the effect of the SUV420H2 inhibitor alone and in combination with current chemotherapy on NEPC. This study will improve our understanding of the development and progression of NEPC and provide new insights into the targeted treatment strategy for NEPC patients. The future development of novel therapeutic agents based on this study will lead to more effective therapy and better quality of life for prostate cancer patients.

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