Androgen Deprivation Therapy Resistance, Fatty Acid Oxidation, and the Role of Beta Hydroxybutyrate
Abstract
For prostate cancer (PCa), androgen deprivation therapy (ADT) (eg. abiraterone acetate and enzalutamide) is the standard systemic treatment. Although initially effective, within 2-3 years of treatment, most patients will develop castration resistant prostate cancer (CRPC). Although mechanisms that promote CRPC are uncertain, it is noted that ADT confers a selective pressure. While most research has focused on PCa epithelia, our lab has shown that there is a selective pressure over the surrounding stroma as well. In essence, these fibroblasts co-evolve to support tumor growth under adverse conditions. Regulation of fatty acid oxidation (FAO) has been identified as a major source of energy in PCa. In fact, clinical studies have shown that enzymes involved in the ketogenic pathway are increased in PCa progression. Interestingly, we found that ketone body production was increased in fibroblasts when exposed to ADT, while its utilization by adjacent epithelia was promoted. Ketone bodies like beta-hydroxybutyrate (BHB) serve as a source of energy but there is ongoing evidence of its importance as a signaling molecule, HDAC inhibitor and histone modifier. Given that BHB can have an important pharmacological role in cancer, we sought to investigate the role of this molecule in CRPC. Preliminary data from our lab shows that ADT non-responsive patients have lower levels of BHB in serum which was in concert with the observed elevated BHB utilization by epithelia in culture. Therefore, we hypothesize that FAO modulation through ADT promotes CRPC phenotype. Blockade of fatty acid metabolism in stroma can sensitize PCa epithelial cells to enzalutamide. Our broad objective is to elucidate mechanisms that promote CRPC by studying the role of FAO in stromal-epithelia interaction.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1121654
Entities
People
- Krizia R. Rivera
Organizations
- Cedars-Sinai Medical Center