Grant: Project Grant - Priority Announcement: Cancer Research

Most prostate cancer relies on androgen receptor (AR) signaling for growth and survival. Therefore, targeting AR signaling had achieved success in the treatment of prostate cancer. Unfortunately, about 20% of patients' tumor eventually come back in a more aggressive form, which is called neuroendocrine prostate cancer (NEPC). This type of tumor loses the dependence on AR signaling and, therefore, is resistant to anti-AR therapy. Currently, standard chemotherapy is the only option available for NEPC, and its benefit is short-lived. Therefore, new therapeutic targets and more effective treatments are urgently needed to improve the management of NEPC. In the last few years, we and other groups have discovered the alterations of a few molecules in terminal NEPC. However, the master molecules that control the NEPC development are still not clear. In view of this, we developed a state-of-the-art pre-clinical model of NEPC, which gives us unprecedented levels of accuracy in monitoring how NEPC develops and progresses. Using this model and advanced single-cell molecular analyses, we have discovered a novel key regulator called PROX1, whose alteration is an early event of NEPC development. In our pilot study, we have preliminarily confirmed its increased expression in clinical NEPC samples and demonstrated its function associated with NEPC. These results suggest that PROX1 may play an important role in NEPC development and progression. In the proposed study, we will further confirm the function of PROX1 and thoroughly investigate the impacts of PROX1 on multiple aspects of NEPC biology. When successful, this study will significantly improve our understanding of NEPC and also provide new insights for the precision treatment strategy for prostate cancer patients. Identification of PROX1 as a novel therapeutic target in this study will pave the road for more effective therapy to improve the quality of life of prostate cancer patients.