Integrating proteogenomic analysis in immunotherapy-treated kidney cancer patients

• Grant number: 23/12970-6
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: CNPq
• Principal Investigator: Leandro Machado Colli
• Grantee: Alison Luis Eburneo Pereira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/01274-9 - Proteogenomic evaluation of patients with Kidney Cancer treated with immunotherapy, AP.R

Abstract

Renal cell carcinoma (RCC) accounts for 2 to 3% of all cancer cases globally, primarily affecting Western countries. Among RCC subtypes, clear cell renal carcinoma (ccRCC) represents approximately 85% of cases. Current treatment strategies predominantly involve targeting vascular endothelial growth factor (VEGF) and employing novel immunotherapeutic agents. Notably, immune checkpoint inhibitors (ICIs) have emerged as the frontline therapy for ccRCC, yielding promising clinical outcomes. These ICIs, including ipilimumab (targeting CTLA-4) and nivolumab (targeting PD-1), have significantly impacted kidney cancer treatment.Despite the remarkable progress in ccRCC therapy, several challenges persist. Approximately 44% of cancer patients in the United States may be eligible for ICI therapy, yet only 12% respond to it. Moreover, resistance mechanisms to ICIs remain incompletely understood, with some patients experiencing complete tumor regression while others suffer from hyperprogression. Consequently, there is a pressing need to elucidate the mechanisms underlying resistance and identify new molecular targets. The CLARA study, an ongoing initiative, seeks to address these challenges by enrolling one hundred metastatic kidney cancer patients for immunotherapy treatment. The study's primary objective is to uncover somatic and germline mechanisms influencing treatment response and resistance. This research project integrates large-scale proteogenomic analyses into its methodology. In addition to collecting exome, transcriptome, methylome, microbiome, and cellular data, the study incorporates proteomics and phosphoproteomics analyses. To achieve this, biopsy tissues from a subset of 40 to 100 patients undergo mass spectrometry analysis. Proteomic profiling is conducted on plasma samples, which are immunodepleted for high-abundance proteins. Patients are classified into responder and non-responder groups based on their treatment outcomes. The quantitative strategy employed utilizes isobaric labeling with either 6 or 10 channels (TMT). This project holds significant potential to enhance our understanding of immunotherapy response mechanisms and identify potential prognostic biomarkers in kidney cancer tissue samples. Ultimately, it aims to influence kidney cancer care by elucidating molecular signatures indicative of treatment response.