Dietary interventions selectively target dysregulated metabolism and reveal metabolic vulnerabilities in preclinical models of advanced renal cell carcinoma.

e16545 Background: Long-term toxicities and acquired resistance to targeted therapies represent a critical clinical challenge for the treatment of advanced clear cell and non-clear cell renal cell carcinoma (RCC), thus highlighting the need for novel therapeutic strategies. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of RCC. As diet has been reported to alter the availability of circulating metabolites available to tumors, dietary interventions represent an innovative strategy to selectively target metabolically dysregulated tumors. Unfortunately, tumor cell plasticity, intratumor heterogeneity, and a lack of understanding regarding metabolic vulnerabilities in tumors are a critical roadblock in the use of dietary restrictions in patients. Therefore, the overall goals of the present study were to better understand nutrient utilization and metabolic dysfunction in RCC to provide biologic rationale for incorporating dietary interventions with standard cancer care. Methods: Using Seahorse, immunohistochemistry, immunofluorescence, metabolomics, and transcriptomics in patient-derived cell lines and murine xenograft models, we investigated the impact protein restriction and alternate day fasting have on energy dynamics in preclinical models of clear cell and translocation RCC. Results: Interestingly, regardless of inherent metabolic phenotype, alternate day fasting was more effective than protein restriction at reducing tumor growth in vivo. Integrated multi-omics analyses of these tumors revealed increased bile acid metabolism with alternate day fasting, indicating a potential tumor suppressive role for these metabolites. Surprisingly, alternate day fasting induced a strong reduction of circulating amino acids that was not observed with protein restriction. Similarly, protein restriction significantly reduced serum triglyceride levels which were not observed in the alternate day fasting group to the same extent. Furthermore, analysis of non-tumor bearing animals revealed distinct metabolite signatures for each dietary restriction that can be easily detected in the blood as a marker of the metabolic state of the host during treatment. Ongoing combination studies with either protein or calorie restriction and targeted therapies, such as standard of care receptor tyrosine-kinase inhibitors, suggest the benefit of using dietary interventions as an adjunct therapy in RCC. Conclusions: Overall, these studies reveal that selective dietary interventions alter the metabolic landscape of RCC and expose vulnerabilities that can be exploited further with targeted therapy.