MODL-33. AN ANIMAL MODEL OF GLI2-AMPLIFIED MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is the most common malignant brain tumor affecting children. Among known subtypes of MB, GLI2-amplified SHH-MB associated with P53 mutations has worst prognosis, and a 5-year survival rate less than 30%. Moreover, MBs are non-responsive to SMO inhibitors, only targeted treatment option available for SHH-MB. To address this gap, there an urgent need identify novel potential therapeutic targets, effort that requires better understanding key cellular molecular mechanisms underlying MB. end, we generated mouse model MB identified GL12 as critical driver tumorigenesis, granule cell progenitors (GCPs) cells origin. We further found GLI2 specifically drives embryonic, but not neonatal, Math1+ GCPs form tumors. An scRNA-seq analysis revealed MAPK pathway activation in embryonic GCPs. The was activated human GLI2-driven tumors, MEK/ERK inhibitor significantly inhibited vivo. Based on these findings, hypothesize originates from specific population during discrete temporal interval cerebellar development, targeting MAPK/MEK/ERK components represents approach