Patient-Derived Orthotopic Xenografts and Cell Lines from Pediatric High-Grade Glioma Recapitulate the Heterogeneity of Histopathology, Molecular Signatures, and Drug Response
He, C.; Xu, K.; Zhu, X.; Dunphy, P. S.; Gudenas, B.; Lin, W.; Twarog, N.; Hover, L. D.; Kwon, C.-H.; Kasper, L. H.; Zhang, J.; Li, X.; Dalton, J.; Jonchere, B.; Mercer, K. S.; Currier, D. G.; Caufield, W.; Wang, Y.; Broniscer, A.; Wetmore, C.; Upadhyaya, S. A.; Qaddoumi, I.; Klimo, P.; Boop, F.; Gajjar, A.; Zhang, J.; Orr, B. A.; Robinson, G. W.; Monje, M.; Freeman, B. B.; Roussel, M. F.; Northcott, P. A.; Chen, T.; Rankovic, Z.; Wu, G.; Chiang, J.; Tinkle, C. L.; Shelat, A. A.; Baker, S. J.
Show abstract
Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. We established 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulated histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and included rare subgroups not well-represented by existing models. We deployed 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predicted variable in vivo response to inhibitors of PI3K/mTOR and MEK signaling pathways. These unique new models and an online interactive data portal to enable exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.
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