Elucidating and Pharmacologic Targeting of Coexisting Diffuse Midline Subpopulation Dependencies

Diffuse Midline Glioma (DMG) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, their treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potential orthogonal drug sensitivities. To address it, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic dependencies of seven coexisting subpopulations identified from tumor biopsies. We then leveraged perturbational profiles of 372 clinically relevant drugs to identify those capable of inverting the activity of subpopulation specific MRs and validated their specificity in vivo. While individual drugs predicted by the analysis to target individual subpopulations—such as avapritinib, larotrectinib, and ruxolitinib—produced only modest tumor growth reduction in orthotopic allograft models, they systemic co-administration induced highly significant survival extension.