In Vitro and In Vivo Approaches for Developing Novel Blood-Brain Barrier-Penetrant Compounds for the Treatment of Pediatric Medulloblastoma

• Grant number: 25/05337-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Carlos Alberto Scrideli
• Grantee: Marina Ferreira Cândido
• Supervisor: Baoli Hu
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Upmc Children'S Hospital Of Pittsburgh, United States
• Associated to the scholarship: 23/02914-1 - Screening of cross the blood-brain barrier drugs in identification of pediatric medulloblastoma new therapies, BP.DR

Abstract

Medulloblastoma (MB) is the most common malignant central nervous system (CNS) tumor in children, with molecularly diverse subgroups that influence prognosis and therapeutic response. Despite advancements in treatment, long-term survivors often face significant challenges, including endocrine complications, cognitive deficits, and debilitating long-term side effects. Relapse and chemoresistance further contribute to the high mortality rates in MB. One of the primary obstacles in treating MB is the limited ability of conventional chemotherapeutic agents to cross the blood-brain barrier (BBB) and to achieve effective therapeutic concentrations within the CNS. This project addresses these challenges by screening compounds capable of crossing the BBB. The previous results started from a library of 274 compounds known to penetrate the BBB and assess their effects through image-based analysis at 6 and 24 hours using the High Content Screening (HCS) ImageXpress Micro XLS platform. We identified the candidate compounds based on their effectiveness in medulloblastoma (MB) cell lines representing the subgroups Group 3/4, SHH-TP53 mutated, and SHH-TP53 wild-type. In the next stage, the selected drugs, Rezivertinib and BMS-202, will be evaluated in specific cell lines of the G3 molecular subgroup. Subsequently, we will explore their therapeutic potential using two MB animal models: the orthotopic xenograft model and the virus-induced spontaneous model. By identifying and focusing on the most promising compounds, this project seeks to advance the understanding of MB biology and uncover new therapeutic strategies to improve outcomes for children with this challenging disease. The findings will provide a foundation for future preclinical and clinical research efforts, addressing the urgent need for safer and more effective treatments for pediatric medulloblastoma. (AU)