Mechanism by which ketogenic diet uncouples tumor growth and overall survival - The overarching goal of this proposal is to add to the understanding of the complex interaction between the tumor and the host organism to facilitate new therapeutic approaches in cancer medicine. Specifically, we aim to establish the mechanistic explanation for the observation in two IL-6 associated murine models of cancer cachexia that KD delays tumor growth but accelerates cancer cachexia and shortens survival. We discovered that this uncoupling may be a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of LPPs and, consequently, saturation of the glutathione system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. The proposal seeks to build on these discoveries in three ways. First, we will determine specific polyunsaturated fat enriched diets and ferroptosis inducing drugs, including licensed medications, that exacerbate the anti-cancer effect. Second, after validating that glucocorticoid deficiency is a critical component of survival reduction of the host organism, using plasma, liver, and adrenal focused assays, we will use systematic pharmacological rescue experiments to enable a therapeutic window for KD intervention. Third, we will track how oxidative stress induced GDF-15 elevations may conspire with IL-6 elevations to drive cachexia associated anorexia via neuronal circuits and thereby cause the negative energy balance that accelerates cachexia onset in KD fed mice. The results of this research may be of interest to scientists and medical professionals. A combination of administration of synthetic GCs may improve food intake, normalizes glucose homeostasis and utilization of nutritional substances, delay the onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while not counteracting the reduced tumor growth induced by the KD-induced ferroptosis. These studies will emphasize the importance of considering the impact of cancer treatments on the host and the tumor.
