2327 - Characterization and pre-clinical modeling of genetic aberrations in pediatric gliomas

Background

Gliomas are the most common CNS tumors in pediatric patients. Despite extensive efforts, the efficacy of the traditional treatments is limited and the overall prognosis is poor. Data from various studies have indicated a genetic diversity between Pediatric and adult gliomas that may imply for the need of dedicated therapeutic approaches for pediatric gliomas. Using whole-genome sequencing, we have identified a wide variety of genetic alterations in low-grade and high-grade pediatric glioma patients that were found to be of interest in terms of their pattern of occurrence and the availability of targeted inhibitors. These genetic aberrations include novel point mutations, gene fusions and duplications in oncogenic factors such as NTRK2 and FGFR1. In order to study the role of this mutated genes in pediatric glioma and to identify and pre-clinically test new therapeutic targets, in vivo models recapitulating the human disease are required.

Methods

In order to validate the role of the selected mutated genes in pediatric tumorigenesis we cloned these genetic aberrations into Cre-inducible lentiviral vectors and injected them directly into the brain of Cre transgenic post-natal 1 (PN1) pups. In vitro, we used the same lentiviral vectors to transduce embryonic neural stem cells to assess their transformation capacity.

Results

We generated a series of novel pediatric glioma models with different combinations of oncogenes and tumor suppressor genes that leads to high mortality rate. Characterization of these tumors by immunofluorescence staining was consistent with common glioma markers. We also established primary cell lines from the generated tumors that are now being used for functional testing of specific inhibitors. In addition, we performed RNAseq analysis in order to assess the human relevance of these generated mouse models and to elucidate the mechanism of action of these mutations.

Conclusions

We were able to generate novel pediatric glioma mouse models that can be used to examine selected mutations found in human pediatric gliomas and serve as a pre-clinical tool for testing novel therapeutic targets.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

DKFZ-MOST grant.

Disclosure

All authors have declared no conflicts of interest.