Disrupting Coupled Redox - Lipid Adaptations in Radioresistant Head and Neck Cancer

About This Grant

SUMMARY Resistance to radiotherapy (RT) and limited response to immunotherapies remain leading causes of mortality in head and neck cancer (HNC) patients. Epidemiological evidence links dietary fats to increased HNC risk, yet the relationship between lipid metabolism and RT sensitivity remains unclear. Through a novel personalized genome-scale metabolic modeling platform that simulated hundreds of cancer patients, redox and lipid metabolism emerged as critical determinants of resistance to RT with special emphasis on mitochondrial NADPH production and dietary polyunsaturated fatty acids (PUFAs). The overarching hypothesis of this project posits that targeting reprogrammed tumor redox and lipid metabolism through a combination of molecular therapies and diet will enhance RT efficacy by leading to elevated DNA damage, improved antitumor immunity, and tumor cell death. Three specific aims are proposed: 1) investigate ferroptosis as the mechanism of RT-sensitization via selective targeting of mitochondrial NADPH metabolism; 2) characterize RT responses associated with dietary and pharmacological redox lipid reprogramming; and 3) assess spatial heterogeneity of redox and lipid metabolism and its relation to immune modulating tumor microenvironment (TME). These aims will be executed through an integrative approach that merges new flux balance analysis techniques that account for spatial heterogeneity with detailed nutrient transport description. The models will inform experimental testing of new therapeutic targets, predict patient-specific responses, and quantify the impact of mitochondrial redox metabolism and dietary lipids on RT outcomes. Results are expected to guide clinical protocols, improving survival for HNC patients with radiation resistant tumors. Mouse models will be used to test modeling-informed hypotheses of redox and lipid modifier diets/drugs alone and in combination, ultimately to guide reprogramming of tumor immune environment and to sensitize tumors to RT.