Abstract 5168: Tumor metabolism as a driver of lethal prostate cancer

Abstract

Abstract BACKGROUND: Recent evidence suggests that dysregulation of tumor metabolism is a key feature in the progression of normal prostate epithelium to cancer, and may also reflect disease aggressiveness and metastatic potential. Identifying the altered metabolic processes driving prostate cancer progression is of particular importance in understanding the biology of this disease. METHODS: mRNA was extracted from the tumors of 404 participants of the Health Professionals Follow-up Study and the Physicians’ Health Study diagnosed with incident prostate cancer (113 lethal (prostate cancer death or metastases) and 291 non-lethal cases), and from adjacent histologically normal tissue available for 202 of these cases. mRNA expression was analyzed for 426 metabolic genes encoding enzymes involved in seven metabolic pathways: Fatty Acid metabolism, Glycolysis/Gluconeogenesis, Oxidative Phosphorylation, Pentose Phosphate, Purine metabolism, Pyrimidine metabolism and the TCA cycle. Gene and pathway-level differences in expression between lethal and non-lethal tumors were assessed, and the findings compared to the expression patterns in adjacent normal tissue. Potential confounders and effect modifiers including cohort, age, year of diagnosis, BMI at diagnosis, clinical tumor stage and Gleason grade were explored and multiple testing was accounted for. RESULTS: Two thirds (99/130) of the genes significantly (p<0.05) associated with lethality were overexpressed in the lethal compared to non-lethal tumors, including POLR2K (p = 5.8×10-9), RRM2 (p = 7.7×10-9), ATP6V1A (p = 7.8×10-8) and POLE2 (p = 7.4×10-7). ALDH2 (p = 4.7×10-8) and PDE4DE (p = 7.1×10-8) were the top genes expressed at lower levels in lethal vs. non-lethal cancer. Purine metabolism (p = 5.6×10-9) Pyrimidine metabolism (p = 1.3×10-7) and Oxidative Phosphorylation (p = 5.3×10-6) were the metabolic pathways most strongly upregulated in lethal tumors, while Glycolysis/Gluconeogenesis (p = 8.7×10-12) was inversely associated with lethality. There was no difference in expression of metabolic genes in normal adjacent tissue among the lethal compared to non-lethal cases, however genes in the Pentose Phosphate, Glycolysis/Gluconeogenesis and Fatty acid metabolism pathways were differentially expressed in normal compared to tumor tissue. Results were robust to adjustment for, and stratification by potential confounders including Gleason grade. CONCLUSIONS: These results support the hypothesis that metabolic changes in tumors may have utility in predicting and understanding lethality. A better comprehension of the dysregulation in specific metabolic genes and pathways may offer novel therapeutic targets for the treatment of prostate cancer. Citation Format: Rachel S. Kelly, Jennifer A. Sinnott, Jennifer R. Rider, Ericka Ebot, Travis Gerke, Kathryn Penney, Michaela Bowden, Massimo Loda, Philip W. Kantoff, Neil E. Martin, Edward L. Giovannucci, Andreas Pettersson Pettersson, Svitlana Tyekucheva, Kathryn M. Wilson, Matthew Vander Heiden, Lorelei A. Mucci. Tumor metabolism as a driver of lethal prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5168. doi:10.1158/1538-7445.AM2015-5168