Ketogenic diets, which are low in protein and carbohydrates and high in fats, result in elevated ketones (2-hydroxybuturate and acetoacetate;precursors to Acetyl-CoA) forcing cells to rely more heavily on mitochondrial metabolism for energy production. It has been hypothesized that cancer cells, relative to normal cells, exist in a condition of chronic metabolic oxidative stress mediated by O2"- and H2O2, with a major site of pro-oxidant production being mitochondrial electron transport chain complexes. If cancer cells (relative to normal cells) have defective mitochondrial O2 metabolism that results in chronic metabolic oxidative stress and ketogenic diets force cancer cells to rely more heavily on mitochondrial O2 metabolism, then ketogenic diets would be expected to selectively cause oxidative stress in cancer cells which in turn would be expected to selectively sensitize cancer cells to conventional cancer therapeutic agents that cause cell killing via oxidative stress. The current proposal will test the hypothesis that ketogenic diets enhance the anti-cancer effects of radio-chemo-therapy combined with inhibitors of glucose metabolism via metabolic oxidative stress. This hypothesis will be tested in two specific aims the first of which will determine if 2DG-induced radio-chemo-sensitization can be enhanced in vitro with 2- hydroxybuturate and/or acetoacetate in human head and neck cancer cells (with CIS) and pancreatic cancer cells (with gemcitabine) via a mechanism involving O27- and H2O2 mediated metabolic oxidative stress. The second aim will determine if ketogenic diets can enhance 2DG-induced radio and/or chemo- sensitization in vivo in human tumor xenograft models of pancreatic and head and neck cancer via metabolic oxidative stress. If chemo-radio-sensitization caused by inhibitors of glucose and hydroperoxide metabolism combined with ketogenic diets can be confirmed to be caused by metabolic oxidative stress, this work could provide the first biochemical rationale for using relatively non-toxic dietary interventions aimed at selectively enhancing oxidative stress in cancer cells combined with conventional anti-cancer agents for the purpose of enhancing cancer therapy based on fundamental differences between cancer and normal cell oxidative metabolism. PUBLIC HEALTH RELEVANCE: Project Narrative: The observation that Increase levels of reactive oxygen species in cancer cells may compensated for by increases in glucose metabolism has led to the idea that cancer cells may have fundamental defects in oxidative metabolism that can be exploited to improve cancer therapy with dietary manipulations. The current proposal will test the hypothesis that ketogenic diets enhance the anti-cancer effects of radio-chemo-therapy combined with inhibitors of glucose metabolism via metabolic oxidative stress. If chemo-radio-sensitization caused by ketogenic diets combined with inhibitors of glucose metabolism can be confirmed to be caused by metabolic oxidative stress, this work could provide a novel biochemical rationale for using dietary interventions to selectively enhance oxidative stress in cancer cells for the purpose of improving conventional cancer therapies based on fundamental differences between cancer and normal cell oxidative metabolism.