Medulloblastoma (MB) is the most malignant pediatric brain tumor, accounting for ~20% of all primary pediatric nervous system neoplasms. Four-subtypes (WNT, SHH, Group-3, Group-4) have been discovered via comprehensive genomics data analysis. Groups-3/4, accounting for 60% of MBs, have poor outcomes. Current therapies (surgery, radiation and chemotherapies) cause permanent impairment on brain development. Identifying targeted therapies with reduced toxicity represent a significant unmed medical need. The challenge is the driver signaling pathways underlying Groups-3/4 remain unclear, though some non-druggable biomarkers have been reported. Our goal is to discover effective targeted therapies for Pediatric MBs.
· Uncover driver signaling pathways underlying Groups-3/4 using a novel systems biology signaling convergence model; and identify novel combinatory therapies with less toxicity and more efficacy using a novel pharmacology mapping model, integrating multi-evidence of thousands of drugs and signaling network topology from millings of combination possibilities (infeasible to experimentally screen combinations).
· Evaluate top prioritized combinations and mechanism of synergy using in vitro and in vivo disease models of Groups-3/4.
Potential impact on child health
Our aims are consistent with objectives of the McDonnell Pediatric Cancer Center, “gaining an understanding of the genetics and biology of childhood cancers and developing more targeted and less toxic treatments.”