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

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. These genetic aberrations include novel point mutations, gene fusions and duplications in oncogenic factors such as NTRK2 and FGFR1. In order to validate the role of these genetic aberrations in pediatric gliomas formation, we generated novel mice models by cloning the mutated genes into Cre/loxP-inducible lentivirus vectors and injecting them into the brain of postnatal day one mice pups, or by in uterus electroporation at E-13.5. The obtained tumors were characterized by RNAseq, immunofluorescence and western blot, unveiling their mechanism of action and revealing possible new inhibition points. Next, we established murine tumor derived cell lines and transplantable in vivo models, which serve as pre-clinical models to test clinically approved drugs that successfully reduced the tumorigenic function of the selected aberrations. Overall, we believe that this project can lead from the genomic discovery of novel driving events in pediatric glioma and through its modeling to the identification and testing of new therapeutic options for the treatment of these malignant tumors.