Grant: Project Grant

The male hormone, testosterone is the primary driver of prostate cancer (PCa). This androgen hormone sustains PCa growth and survival by activating the androgen receptor. Drugs called androgen receptor targeted agents (ARTAs) are the primary treatment for PCa not cured by surgery or radiation therapy. While initially effective, PCa inevitably becomes therapy resistant. ARTA-resistance is often because the cancer starts producing its own androgens. Cholesterol is essential for androgen production and supporting other essential cell growth requirements. Scavenger Receptor Class B Member 1 (SR-B1) is critical for cholesterol uptake by tissues that synthesize androgens, such as testis and the adrenal glands. We have shown that SR-B1 expression is increased in PCa, further increased in ARTA-resistant PCa, and is linked to high risk disease. Increased SR-B1 expression is not due to gene amplification or mutation. Rather, we have identified potential changes to the way the gene is epigenetically regulated. Epigenetic regulation is how different cells control which genes are expressed. We hypothesize that SR-B1 expression by PCa is caused by epigenetic reprogramming, and that suppressing SR-B1 expression or activity will cause toxic stress by decreasing cholesterol essential for PCa growth and survival. We will test this hypothesis by examining epigenetic mapping of the SR-B1 gene in benign prostate and PCa tissues and cell models. We will use genetic and pharmacologic tools to determine precisely how SR-B1 affects specific cell stress responses in androgen-sensitive and ARTA-resistant PCa models. We will also perform a gene knock out screen in PCa cells to determine what other cellular pathways might act cooperatively to kill prostate cancers that rely on SR-B1 expression. This project will provide a clear understanding of how SR-B1 regulates ARTA-resistance and identify novel therapeutic opportunities that might be able to effect a cure for this lethal disease state.