Utilization of Fasting Mimicking Diets to Treat and Prevent Clear Cell Renal Cell Carcinoma

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Von Hippel Lindau (VHL) disease is a rare genetic disorder effecting 1 in 36,000 Americans every year with an average life expectancy of 49 years. Currently, there is no long-term treatment for the spontaneous tumors that patients develop across their body, markedly, kidneys in the form of Clear Cell Renal Cell Carcinoma (ccRCC). With limited pharmacological treatments available dietary modifications have become a topic of interest for several cancer types. Notably a ketogenic diet containing high fat (>80%) and low carbohydrate (<10%) alters metabolism at the organ and cellular level to preferentially utilize fats and ketones for fuel. Recent data I have generated suggests that two diets that generate the ketone beta-hydroxybutyrate (BHB); the Cyclical Ketogenic Diet (CKD) and a diet containing pre-ketone 1,3 butanediol (BD), both shrink subcutaneous tumors in NCr Nude mice from the human ccRCC cell line 7860. Furthermore, nude mice with orthotopic 7860 tumors who are fed a CKD had a life expectancy 58% longer than those on a standard diet (SD). When mice were fed a CKD for two weeks before orthotopic injections of 7860, 9/10 kidneys in CKD fed mice showed minimal tumor signal and overall tumor growth was significantly lower than that of tumor growth in kidneys in SD fed mice, implying that a CKD has significant prophylactic capabilities against ccRCC. In-vitro analysis of several human ccRCC cell lines shows that BHB addition halts growth of these cells but does not significantly affect growth of non-cancerous kidney cells. Furthermore, BHB addition to ccRCC cells shows significant changes in several key markers of ferroptosis such as TFRC and SLC7A11 with BODIPY C11 and 4-hydroxynonenal (4-HN) being upregulated in tumors as well as cells and halting growth in-vitro. It is important to note that VHL loss has recently been associated with an increase sensitivity to ferroptosis. With these data in mind we hypothesize that BHB generated from a CKD and BD alters gene expression and metabolic processes to induce ferroptosis in ccRCC cancer cells. Also, that this mechanism could be generalized to several cancers associated with VHL mutations and potentially be utilized as a prophylactic to prevent many tumors that arise in those with VHL disease. With these data to be generated I hope to publish in high impact relevant journals such as Cancer Metabolism, apply for additional federal funding, and establish this mechanism in more robust pre-clinical settings to lay the groundwork to make real life impacts on patients.