Targeting Castration Resistant Prostate Cancer via Potent Inhibition of Signaling Lipids

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Summary Metastatic castration resistant prostate cancer is uniformly fatal, representing the second-leading cause of cancer-related death among men in the United States. Despite therapeutic advances with docetaxel, abiraterone and enzalutamide, prostate cancer progression to lethal castration-resistant prostate cancer (CRPC) remains a major clinical problem. Rapidly proliferating cancer cells upregulate de novo lipogenesis and cholesterol synthesis pathways in order to provide lipids for membrane formation and lipid modification of proteins and to support energy production. The sterol regulatory element binding proteins (SREBPs) are master regulatory transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. The SREBPs are frequently overexpressed in prostate cancer and other solid tumors and are associated with tumor aggressiveness and unfavorable outcomes. Interestingly, emerging studies suggest that in African American (AA) prostate cancer patients - who already have 1.6 times higher prostate cancer incidence and 2.6 times higher mortality from prostate cancer than Caucasian males - the androgen receptor and PI3K/Akt/mTOR signaling pathways are more active than in Caucasian prostate cancer patients, frequently resulting in even greater increase in lipid metabolism. Androgen receptor and the PI3K/Akt signaling can activate the transcription factor MNX1, leading to induction of SREBP1, which controls expression of numerous lipogenic genes including FASN, and alters the metabolic state of the prostate cancer cell. Inactivation of SREBPs represents a novel mechanism by which metabolically-driven tumors can be targeted. The overarching goal of this preclinical study is to establish key proof-of-concept efficacy and safety data for the use of SREBP inhibitors against prostate cancer cells, using extensive in vitro and in vivo models. Our proposed studies are focused on 1) defining the function of SREBPs in prostate cancer and identifying biologically significant lipid products of SREBP activation, 2) evaluating effects and mechanisms of a small molecule inhibitor of SREBP in vitro, and 3) assessing the anticancer activity of SREBP inhibitors alone and in combination with existing drugs, using cell line xenograft and innovative patient-derived xenograft models of prostate cancer.