Tumors of the central nervous system are the most common form of childhood malignancy, and remain the leading cause of cancer-related morbidity and mortality in children. Despite extensive efforts, the efficacy of the traditional treatments is limited and the overall prognosis is poor. In recent years it has become apparent that pediatric gliomas differ from their adult counterparts, explaining in part why the therapies extrapolated from adult gliomas have failed, and further supporting the need to understand the biology of the childhood disease. Deep sequencing studies on brain tumor specimens within various cancer genome consortia (e.g. ICGC PedBrain, TCGA) has yielded a wealth of information about molecular aberrations that had accumulated in tumors. This has unravelled a considerable degree of heterogeneity and thus resulted in the delineation of different molecular subgroups. Furthermore, it has provided comprehensive insights into tumor genomes deduction. Nevertheless, validation of oncogenically relevant genes and therapeutically actionable targets in an in vivo context still remains a major challenge in the process of developing novel treatment approaches. We have generated state-of-the-art in vivo methodologies based on somatic gene transfer for generating animal models faithfully recapitulating the molecular and clinical characteristics of the respective human counterpart. In this study, we focused on NTRK2 fusions and FGFR1 mutations and characterized the tumors obtained by either in utero electroporation or lentiviral injection into postnatal (P0-P1) mice. Tumor derived cell lines grown in stem cell media were tested for conventional therapies (e.g. TMZ) and screening of available small inhibitor compounds. In addition, we have characterized the tumor microenvironment of these lesions, mainly the infiltrating immune cell populations. This study thus represents an important contribution to the understanding of pediatric glioma biology as well as to translational efforts in developing new treatment approaches for these malignant tumors.

Citation Format: Or Zohar, Itai Moshe, Ismer Britta, David T. Jones, Dinorah Friedmann-Morvinski. Generation, characterization and functional validation of novel preclinical models for human pediatric glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3042.