Metabolic Vulnerability of MYC-Amplified Group 3 Medulloblastoma: Rationale for Stepwise Combined Therapy

MYC-amplified Group 3 medulloblastoma carries dismal prognosis with less than 50% five-year survival despite intensive multimodal therapy. This Perspective synthesizes emerging evidence on metabolic vulnerabilities specific to this subgroup, proposing a stepwise therapeutic framework. We identify five convergent vulnerabilities: mitochondrial oxidative stress via the MPC-SOD2-MYC axis, serine-glycine biosynthesis dependency through PHGDH overexpression, glutamine addiction for anaplerosis, lipid metabolism reprogramming, and epigenetic-metabolic crosstalk. Integration of recent findings demonstrating that dietary serine-glycine restriction combined with PHGDH inhibition extends survival by 50% in preclinical models provides foundation for clinical translation. We propose a Metabolic Vulnerability Index 2.0 for patient stratification and outline a three-phase protocol combining metabolic sensitization with conventional therapy. This framework offers a roadmap for precision metabolic oncology trials in this devastating pediatric malignancy.