In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 16_Supplement ( 2016-08-15), p. A07-A07
Abstract:
Recent genomic studies have revealed multiple molecular subtypes of pediatric brain cancers that are not only biologically but also clinically distinct. In order to develop novel treatment strategies for these often fatal diseases we need more preclinical models like orthotopic patient-derived xenograft (PDX) models that correctly reflect the many different tumor types. Prior to drug selection and testing, extensive molecular characterizations are needed to precisely assign a distinct molecular subgroup to each PDX model and to learn about its targetable oncogenic drivers. In an international effort we aim to characterize a large repertoire of PDX models reflecting the many different molecular subtypes of pediatric brain cancer. Thus far, we have collected and characterized 64 established PDX models from 6 atypical teratoid rhabdoid tumors (AT/RT), 7 ependymomas (EPN), 16 high-grade gliomas (HGG), 32 medulloblastomas (MB), and 3 primitive neuroectodermal tumors (PNET). All PDX models and their matching primary tumors (if available) are analyzed by whole-exome and low-coverage whole-genome sequencing, as well as DNA methylation and gene expression profiling. The DNA methylation and gene expression data showed that PDX models always cluster together with their respective brain tumor reference samples and in most cases very close to their matching primary tumor. Tumor subtype-specific oncogenic lesions could be detected by both sequencing technologies. By comparing PDX models to their primary tumor, we showed that they retain the molecular subtype, mutations and copy number alterations. Only in rare cases we observed additional aberrations in PDX models such as chromothriptic events in one MB (Group 3) or chromosome 1q gain in one EPN (posterior fossa subtype A). However, these additional aberrations are typical for this tumor subtype and were therefore most likely already present in the primary lesion at a subclonal level. Analysis of our entire cohort identified a 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 MBs. Our molecular characterizations of PDX models provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies of malignant pediatric brain tumors. Citation Format: Sebastian Brabetz, Huriye Seker-Cin, Susanne N. Gröbner, Norman L. Mack, Volker Hovestadt, David T. W. Jones, Till Milde, Madison T. Wise, Jessica M. Rusert, Kyle Pedro, Karina Bloom, Xiao-Nan Li, Robert J. Wechsler-Reya, James M. Olson, Stefan M. Pfister, Marcel Kool. Molecular characterization of patient-derived xenograft models of pediatric brain tumors. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A07.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1557-3265.PDX16-A07
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
