Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Abstract

Prostate cancer (PCa) is the most common cancer in men, and more than 10% of men will be diagnosed with PCa during their lifetime. Patients that are not cured with surgery or radiation are largely treated with endocrine therapies that target androgens or the androgen receptor (AR), a major driver of PCa. In response to androgen deprivation, most PCas progress to castrate resistant PCa, which is treated with anti-androgens like enzalutamide, but tumors still progress and become incurable. Thus, there is a critical need to identify cellular pathways that allow tumors to escape anti-androgen therapies. Epidemiological studies suggest that high-fat diets play important roles in PCa progression. Lipid metabolism rewires the PCa metabolome to support growth and resistance to endocrine therapies, although the exact mechanisms remain obscure. Therapeutic effects have been observed inhibiting several aspects of PCa lipid metabolism: Synthesis, uptake, and oxidation. Since AR remains a driver of PCa in advanced disease, strategies targeting both lipid metabolism and AR are starting to emerge, providing new opportunities to re-sensitize tumors to endocrine therapies with lipid metabolic approaches.

Keywords

• lipid synthesis
• lipid oxidation
• AR
• prostate cancer
• CPT1A
• FASN
• endocrine resistance
• anti-androgens
• dietary lipids
• combination therapy