PCM-16MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS

PCM-16. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS Sebastian Brabetz1, Susanne N. Groebner1, Huriye Seker-Cin1, Norman L. Mack1, Volker Hovestadt1, David T. W. Jones1, Florian Selt1,2, Till Milde1,2, Madison T. Wise3, Jessica M.Rusert4, Kyle Pedro3, Karina Bloom3, Olaf Witt1,2, Sarah E. Leary3, Xiao-Nan Li5, Robert J. Wechsler-Reya4, James M. Olson3, Stefan M. Pfister1,2, and Marcel Kool1; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Center for Individualized Pediatric Oncology (ZIPO) and Pediatric Brain Tumors, Department of Pediatric Oncology, University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany; Fred Hutchinson Cancer Research Center and Seattle Children’s Hospital, Seattle, WA, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Baylor College of Medicine, Houston, TX, USA Orthotopic patient-derived xenograft (PDX) models are an excellent platform for biomarker and preclinical drug development. Prior to drug selection and testing, extensive molecular characterization is needed to precisely determine the distinct molecular subgroup and constellation of genetic alterations for each PDX model, and thus identify its targetable oncogenic drivers. In an international effort we have characterized a large repertoire of PDX models reflecting many different molecular subtypes of pediatric brain tumors and assessed inter-tumoral heterogeneity within these subtypes. Thus far, we have collected and characterized 70 established PDX models from 6 ATRTs, 8 ependymomas, 16 high-grade gliomas, 38 medulloblastomas, and 2 CNS-PNETs. All PDX models and matching primary tumors (if available) have been analyzed by whole-exome and low-coverage wholegenome sequencing, as well as DNA methylation and gene expression profiling.PDXmodels always retain theirmolecular subtypeand in thevastmajority of cases also the mutations and copy number alterations when compared to their primary tumors. Only in rare cases do we observe additional aberrations, which most likely represent outgrowths of subclones from the primary tumor. Analysis of our entire cohort identified an overrepresentation of the most aggressive tumor subtypes, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma. Our molecular characterization of PDX models will provide an unprecedented resource to study tumorbiologyandpave theway for improving treatment strategies forchildren with malignant brain tumors. Neuro-Oncology 18:iii139–iii144, 2016. doi:10.1093/neuonc/now080.16 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.