Comprehensive Proteogenomic Characterization Reveals Clinically Relevant Molecular Subtypes Associated with Medulloblastoma Progression

Current treatment strategies for medulloblastoma remain ineffective due to extensive tumor heterogeneity. In this study, we performed integrated multi-omic characterization to improve the conventional molecular classification of medulloblastoma, leading to the identification of seven refined distinct subtypes. The SHH group was reclassified into two subgroups, SHHα and SHHβ, while group 4 was divided into three subgroups, G4α, G4β, and G4γ. SHH and Group 4 subtypes exhibit two distinct neuronal differentiation trajectories: granular neuron (GN) and unipolar brush cell (UBC) differentiation (SHHβ and G4γ, respectively), both of which associated with more favorable clinical outcome. Furthermore, we uncovered unique proteomic and kinomic properties that conferred increased treatment vulnerabilities to targeted therapeutic interventions against each of the three medulloblastoma subtypes associated with poor clinical outcome. We demonstrated the therapeutic potential of exploiting these vulnerabilities by utilizing a proteasome inhibitor and subtype-specific agents, including CDK1/2, PARP, CLK1, and MET inhibitors. Mechanistic insights were further elucidated through in-depth proteome analyses. In conclusion, our study qualifies the use of proteomic signatures and activation of neuronal differentiation trajectories to tailor selective therapeutic opportunities for distinct subgroups of medulloblastoma patients.