Program Director/Principal Investigator (Last, First, Middle): Ippolito, Joseph Edward PROJECT SUMMARY There is a sex disparity seen in cancers throughout the body where males have both a higher incidence and a higher mortality than females. This is not only true for adults, but is also seen in children as well, suggesting that factors other than the effects of sex hormones may be playing a role in this phenomenon. This is especially true for glioblastomas (GBM) that comprise over 50% of brain tumors and are characterized by resistance to therapies and a dismal prognosis (median survival - 15 months). Because enhanced nutrient consumption and metabolism are critical to enhanced tumorigenesis and its effect on poor patient outcomes, our group investigates the presence of sex differences in cancer metabolism that may be driving the sex disparities that are observed in many cancers. We have uncovered laboratory and clinical evidence demonstrating that male brain tumors have enhanced nutrient uptake and metabolism (specifically sugars and amino acids) compared to female tumors. We have further identified that the largest sex differences in cancer metabolism come from the mitochondria, the part of the cell that is the critical for generating energy and biosynthetic building blocks for the cell for growth. Because metabolism is not only restricted to the tumor, but involves the entire patient, we have investigated the effects of sex differences in nutrition and obesity in cancer patient survival. We have discovered that women with “male-pattern” increased visceral abdominal obesity selectively do much worse compared to all other patients in multiple cancers. These findings suggest that the sex differences that we see in cancers may not only be related to tumor mitochondria, but nutrition and its overall metabolic health of the individual. In this proposal, we will develop new animal models to test the hypothesis that sex differences in mitochondrial activity underlie sex differences in tumor development. Our long term goal is to understand the metabolic basis of sex disparities in cancer patients through a combination of tumor and host metabolism. In the first aim of this proposal, we will use an established model (Nf1-/-/DNp53) for sex differences in GBM and deplete mitochondria in the cancer cells to test for sex differences in cancer cell phenotype and metabolism. In the second aim, we will determine the effects of obesogenic diets on sex differences in brain tumor mitochondrial activity and growth. This research proposal is innovative because it opens up a new paradigm in the oncology field that investigates sex-specific differences in cancer and host metabolism. This proposal will generate new insights into the mechanism behind sex differences in mitochondrial activity and the impact of nutrition on sex differences in the malignant phenotype. We are beginning to develop a platform for novel readily-translatable imaging methods and therapeutic app...