Screening of cross the blood-brain barrier drugs in identification of pediatric medulloblastoma new therapies

• Grant number: 23/02914-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): June 01, 2023
• Effective date (End): November 30, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Carlos Alberto Scrideli
• Grantee: Marina Ferreira Cândido
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Medulloblastoma (MB) is a solid malignant tumour of the central nervous system (CNS) located in the cerebellum, which most affects and kills children. The prognosis and survival rate of patients with MB vary according to molecular subgroups: SHH (Sonic Hedgehog), which represents about 30% of cases, separated into tumours with mutated or wild-type TP53 gene; WNT (Wingless), which corresponds to 10% of cases; and non-SHH and non-WNT tumours, subdivided into groups 3 and 4, being identified in 25% and 35% of patients, respectively. Side effects and endocrine and cognitive sequelae are often observed in survivors, in addition to cases of relapse and chemoresistance that lead to the highest death rate among this disease. The challenges and difficulties in the treatment against MB are found mainly in therapeutic failures due to the inability of conventional chemotherapeutic agents to cross the blood-brain barrier (BBB) and reach their targets in the tumour tissue. Interestingly, the development of a screening of compounds that have proven to bypass the BBB to identify potential antitumor agents or agents that favour the sensitization of tumour cells to conventional chemotherapeutics remains unexplored in MB. Thus, the present work seeks to identify and evaluate drugs that cross the BBB as options for new therapies for MB alone or combined with conventional chemotherapy. To carry out this investigation, we will screen drugs that cross the BBB with the HCS (High Content Screening) methodology, analyzing the viability and effects of these compounds in pediatric MB strains with a worse prognosis in 2D and 3D cultures.