RESEARCH PROJECT 1: DAQING WU

Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PCa), the major cause of PCa mortality. Unfortunately, in most cases, PCa develops chemoresistance and continues progressing, which has no cure. We developed a novel phenotypic screen and discovered bromocriptine, an approved non-oncology drug, as a potent and selective inhibitor of chemoresistant PCa cells. In preliminary studies, we demonstrated that bromocriptine effectively induced cell cycle arrest and cell death in chemoresistant PCa cells via dopamine D2 receptor-dependent and -independent mechanisms. In mouse models, bromocriptine monotherapy was efficacious in suppressing the skeletal growth of chemoresistant PCa. These exciting results support our hypothesis that bromocriptine is a novel and effective subtype-focused precision therapy for chemoresistant PCa. Through this Research Project, we will investigate the mechanism of action and preclinical efficacy of bromocriptine against chemoresistant PCa. Our main objective is to provide solid preclinical evidence supporting bromocriptine as a safe, effective, and affordable care for chemoresistant PCa. To do so, we propose two specific aims. In Aim 1, we will elucidate the mechanism of action of bromocriptine in chemoresistant PCa cells and discover novel molecular targets of bromocriptine. In Aim 2, we propose demonstrating that oral administration of bromocriptine is efficacious against chemoresistant PCa and exhibits excellent safety profiles in preclinical models. With the successful accomplishment of this project, bromocriptine will be well-positioned to be promptly repurposed as a safe, effective, and affordable precision therapy for chemoresistant PCa subtypes. The impact of our research has significant public health implications for improving PCa treatment, decreasing the mortality rate of PCa, and reducing PCa disparity.