Abstract 1786: Metabolic rewiring induced by protein or calorie restriction provides unique therapeutic vulnerabilities in translocation and select clear cell renal cell carcinomas

Abstract While the approval of several combinations with immune checkpoint inhibitors have significantly improved the outcome of kidney cancer patients, advanced clear cell and non-clear cell renal cell carcinoma (RCC) remain a clinical challenge. There has been a longstanding interest in using dysregulated metabolism as a therapeutic target due to its association with the pathogenesis and progression of several cancer types. As one of these highly metabolic tumors, RCC has the potential to greatly benefit from strategies targeting tumor metabolism. Dietary interventions are an innovative adjunct therapy that has the potential to induce a wide range of anti-cancer effects by disrupting metabolism due to the role diet plays in providing tumors with macromolecules for energy metabolism. Unfortunately, tumor cell plasticity, intratumor heterogeneity, and a lack of understanding regarding metabolic vulnerabilities in tumors limit the efficacy of implementing these strategies and a fundamental gap in the field remains as to how basic metabolic requirements of the tumor can be targeted with specific dietary interventions. In this study, the inherent metabolic phenotypes of translocation RCC (tRCC) and clear cell RCC (ccRCC) were characterized by integrating in vivo metabolomics and transcriptomics data, assessing mitochondrial and glycolytic activity in vitro via Seahorse, and performing immunohistochemical analyses of patient samples. Interestingly, the respective mitochondrial and glycolytic dependencies in tRCC and ccRCC patient-derived xenograft (PDX) models appear to influence the response to nutrient deprivation as seen by in vitro assays conducted after amino acid or glucose restriction. Importantly, these results indicate that dietary interventions may be able to selectively target metabolic vulnerabilities in tRCC and ccRCC. 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. Overall, these studies reveal that selective dietary interventions alter the metabolic landscape of RCC and expose vulnerabilities that can be exploited with targeted therapy. As dietary interventions are a safe, affordable, and potentially well tolerated adjunct therapy, we anticipate that the results of these studies will provide the biologic and mechanistic support for translating this strategy to advanced RCC patients. Citation Format: Sabrina A. Orsi, Christopher Rupert, Sean Colligan, Musea Chang, Abbas Jawadwala, Ilaria Delle Fontane, Filomena de Nigris, Roberto Pili. Metabolic rewiring induced by protein or calorie restriction provides unique therapeutic vulnerabilities in translocation and select clear cell renal cell carcinomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1786.