Metabolism reprogramming in Clear Cell Renal Cell Carcinoma's aggressiveness and resistance to sunitinib

• Grant number: 22/05801-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2023
• End date: July 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Céline Marques Pinheiro
• Grantee: Céline Marques Pinheiro
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
• Associated researchers: Flavio Mavignier Cárcano ; Murilo Queiroz de Almeida Bonatelli ; Rui Manuel Vieira Reis

Abstract

Renal Carcinoma is an aggressive cancer and is usually diagnosed in later stages. Clear cell Renal Cell Carcinoma (ccRCC) is the most common subtype of Renal Carcinoma, accounting for about 70% of cases. The ccRCC is mainly characterized by mutation in VHL, a gene that plays an important role in the reprogramming of energy metabolism, among others, by modulating the expression of HIF-1A and HIF-2A. Cell metabolism impacts on most aspects of tumor biology and has been pointed out as a potential therapeutic target for cancer treatment. Importantly, the metabolic reprogramming of tumor cells has also been associated with the response to different antitumor therapies. Thus, this project aims to characterize the metabolic profile and assess its clinical relevance in human samples of ccRCC from patients treated with sunitinib, as well as assess the potential of energy metabolism as a therapeutic target in ccRCC. For that, two methodological approaches will be used: (i) quantification of the expression of genes involved in tumor metabolism and immunometabolism in human ccRCC samples, using NanoString, and association with the clinicopathological characteristics and clinical outcomes of the patients; and (ii) in vitro studies, using the CRISPR9/Cas9 system, to assess the effect of the KO of metabolism-related genes on tumor aggressiveness characteristics of ccRCC. With this project, we expect to identify gene expression signatures that can serve as prognostic and/or response biomarkers to sunitinib in ccRCC, as well as identify potential therapeutic targets related to metabolic alterations in cancer relevant in ccRCC. (AU)