In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1935-1935
Abstract:
[Introduction: Solid tumors of the nervous system are the most common childhood cancers after leukemias. Even though we might be able to cure more and more patients, survivors still severely suffer long-term from the intensive treatments. Therefore, new treatment strategies are urgently needed. Orthotopic patient-derived xenograft (PDX) models are an excellent platform for biomarker and preclinical drug development. However, the rarity of pediatric brain tumors and the multitude of different sub entities hinder the generation of large collection of PDX models of specific entities within single institutions. In order to generate an overview about existing PDX models in the community, we started collecting established PDX models from various centers all over the world and performed extensive molecular characterization to precisely determine the distinct molecular subgroup and constellation of genetic alterations for each PDX model, and thus identify its targetable oncogenic drivers. Material and Methods: PDX models were established and maintained by dissociating tumor material into a single cell suspension and then orthotopically injecting it into the brain of immunodeficient animals. 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 at the German Cancer Research Center (DKFZ). Results and Discussion: 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. 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. Based on our current analysis, the PDX models within the community are not yet covering the entire heterogeneity within the patient population. As a follow up, we aim to make these models and data accessible in a user-friendly manner so that the community can use them for preclinical research. Conclusion: PDX models of pediatric brain tumors are very rare. Our molecular characterization allows researchers all over the world to find the right models for their specific scientific question. Therefore, this work will provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies for children with malignant brain tumors. Citation Format: Sebastian Brabetz, Susanne N. Gröbner, Huriye Seker-Cin, Florian Selt, Till Milde, David T. Jones, Madison T. Wise, Jessica M. Rusert, Kyle Pedro, Andy Strand, Olaf Witt, Sarah E. Leary, Xiao-Nan Li, Robert J. Wechsler-Reya, James M. Olson, Stefan M. Pfister, Marcel Kool. Molecular characterization of orthotopic patient-derived xenograft models of pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1935. doi:10.1158/1538-7445.AM2017-1935
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-1935
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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