DDDR-33. TARGETING TGFΒ PATHWAY DEPENDENCIES IN GROUP 3 MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at < 50%, few recurrent mutations, higher frequency metastasis, no targeted therapies. Amplification MYC (c-myc) activation TGFβ signaling are frequent G3 MB. We hypothesize that pathway contribute to intrinsic resistance MB through deregulation key genes pathways. previously established humanized models for SHH by introducing MYCN or PTCH1 deletions into neuroepithelial stem (NES) cells derived from normal human induced pluripotent (hIPSCs). In this study, we transduced NES TGFb effectors activated (ACVR2A, TGFbR1, TGFb1, TGFb3, SMAD5) alone and/or combination MYC, prioritizing combinations observed patients. Excitingly, both drove tumor formation vivo leading more aggressive tumors. thus describe six new isogenic non-MYC driven next found expressing either TGFβR1 TGFβ1 showed clinical inhibitors, compared alone. To decipher mechanisms resistance, integrated CUT & RUN probe genomic localization relevant histone PTMs RNA-seq analysis cells. discovered a subset upregulated TGFb-driven lines targets demethylase KDM2B. postulate epigenetic remodeling via recruitment other MYC-interacting cofactors culminates transcriptional changes lead disease. Overall, our studies provide insights on identifying therapeutic avenues patients