The role of metabolism in the aggressiveness and sunitinib-resistance in Clear Cell Renal Cell Carcinoma

• Grant number: 22/09996-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Céline Marques Pinheiro
• Grantee: Patrik da Silva Vital
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
• Associated scholarship(s): 24/04272-0 - The role of microenvironment in the aggressiveness and sunitinib-resistance of clear cell renal cell carcinoma, BE.EP.DR

Abstract

Clear-cell renal cell carcinoma (ccRCC), the most lethal type of neoplasia among the urologic malignancies, accounts for 75-85% of all kidney cancers. In clinical practice, even in the era of immunotherapy, sunitinib is often used as the first line of treatment against this neoplasia. However, despite presenting an initial response, about 70% of patients treated with this drug develop resistance within 12 months. Several ccRCC features, such as their preference for aerobic glycolysis, cytoplasmatic accumulation of glycogen and colesterol, oncometabolites accumulation, and the fact that genes often mutated in this neoplasia are involved in cellular metabolism, make ccRCC a primarily metabolic disease. Some of those modification are already associated with sunitinib-resistance development. Objective: This project aims to characterize and evaluate the relevance of metabolism in aggressiveness and sunitinib-resistance in ccRCC patients and cell lines. Material and methods: An association will be performed between clinical-pathological features and clinical outcome of ccRCC patients treated with sunitinib and their expression profile of immunometabolic genes (NanoString). The differential expression of these genes will also be analyzed in ccRCC cell lines before and after sunitinib-resistance development. Finally, cellular parameters such as viability, proliferation, death, migration, and invasion will be evaluated in a sunitinib-resistant ccRCC cell line after the knockout of selected genes involved in tumoral aggressiveness and sunitinib-resistance. Expected results: In the present study, we expect to identify new therapeutic targets and immunometabolic genetic signatures that might serve as prognostic biomarkers or sunitinib-response in ccRCC. (AU)