Investigation and Evaluation of Molecular Mechanisms in the Development of Precision Therapy in Pediatric Medulloblastoma

• Grant number: 24/04065-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Elvis Terci Valera
• Grantee: Victor Wendel da Silva Gonçalves
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Introduction: Pediatric brain tumors represent a significant cause of mortality in this age group. Medulloblastoma (MB) is the most frequently occurring malignant pediatric tumor affecting the Central Nervous System (CNS). Genetically, MBs are classified into four distinct molecular subgroups (WNT, SHH, Group 3, and Group 4). Currently, the histological and molecular characteristics of MB assist in defining risk and therapeutic delineation. Some molecular subgroups (particularly MB Group 3) correlate with worse clinical outcomes, necessitating new therapeutic approaches. Objectives: This study aims to identify new prognostic biomarkers in MBs of Groups 3 and 4; it further intends to validate these biomarkers by correlating them with clinical outcomes and evaluating drugs inhibiting any of the identified target genes. Methods: In silico analysis of differentially expressed genes (DEGs) in different MB subgroups; validation of differential gene expression in molecularly classified MB tumor samples; identification of up-regulated biomarkers in Groups 3 and 4 to be evaluated in in vitro experiments; evaluation of the expression of these biomarkers in MB Group 3 and 4 cell lines (USP-13, D283, Med-114, and D341). Functional testing of inhibitor compounds of selected biomarkers (cell viability - MTT; apoptosis - flow cytometry) in treated, untreated cell lines, and non-tumoral cell control (drug toxicity assessment). Statistical Analysis: Overall survival by Kaplan-Meier method; comparison of survival among MB subgroups by log-rank test. Relevance: It is anticipated that the genes selected in the in silico model, validated in the clinical cohort, and demonstrating an anti-tumoral profile in evaluated cell lines, can guide preclinical tests for unfavorable subgroups of pediatric MBs.