Advancing Medulloblastoma Treatment: Molecular Mechanisms, Drug Repurposing, and Precision Therapies

Abstract

Medulloblastomas are the most common malignant pediatric brain tumors, representing approximately 20% of the central nervous system cancers in children. These tumors are highly heterogeneous and classified into four molecular subgroups-WNT, SHH, Group 3, and Group 4-each with distinct genetic and epigenetic profiles that influence tumor behavior, therapeutic response, and patient outcomes. Advances in molecular diagnostics have improved the subclassification of medulloblastomas, yet treatment outcomes for high-risk subtypes, particularly Group 3, remain poor, with current modalities often associated with severe long-term neurocognitive and systemic toxicities. Effective drug delivery across the blood-brain barrier remains a major hurdle, limiting the clinical efficacy of targeted therapies. Drug repurposing offers a promising strategy to accelerate treatment availability by utilizing US Food and Drug Administration-approved agents, including niclosamide, itraconazole, and arsenic trioxide, to target critical oncogenic pathways and overcome therapeutic resistance. However, challenges such as limited blood-brain barrier penetration and the lack of pediatric-specific pharmacokinetic data persist. Future research should focus on integrating comprehensive molecular profiling to guide personalized therapy selection, optimizing drug-delivery systems, and exploring rational drug combinations. Emerging technologies, including nanotechnology-based delivery systems, CRISPR-mediated gene editing, and chimeric antigen receptor-T cell therapies, hold significant potential for transforming medulloblastoma treatment paradigms but require further refinement to address toxicity, off-target effects, and biomarker development. Advancing innovative, less toxic therapeutic strategies through the integration of molecular diagnostics and precision therapies is essential to improving survival outcomes and quality of life for children with medulloblastomas.