Work

Pcm-16molecular Characterization of Orthotopic Patient-derived Xenograft Models of Pediatric Brain Tumors

Year: 2016

Type: article

Abstract: 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 whole-genome sequencing, as well as DNA methylation and gene expression profiling. PDX models always retain their molecular subtype and in the vast majority 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 tumor biology and pave the way for improving treatment strategies for children with malignant brain tumors.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/now080.16