Abstract
The occurrence and importance of gene fusions in glioma has been appreciated only recently, largely due to high-throughput technologies, and gene fusions have been indicated as one of the major genomic abnormalities in glioblastoma (GBM), the most frequent and aggressive glioma subtype. The functional role of the majority of these alterations is completely unexplored. Recurrent gene fusions involving the Tropomyosin Receptor tyrosine Kinases (TRK) receptor family have been recently described in a variety of tumors, including both pediatric and adult low-grade (LGG) and high-grade gliomas (HGG). Strikingly, 40% of non-brain stem pediatric HGGs in infants have been shown to carry TRK gene fusions, making Trk inhibition an important potential therapeutic intervention in patients in which the current treatment modalities have devastating side effects. For the in vivo study of genomic rearrangements, we have recently generated an innovative mouse model that combines the genome editing capability of the CRISPR/Cas9 system with the somatic gene delivery of the RCAS/tv-a system. By searching the scientific literature we have identified approximately 30 different fusion involving NTRK1, NTRK2 and NTRK3 genes. To discriminate those fusions with tumorigenic potential in gliomas we have performed an in vivo gRNA pair screening. Four different RCAS-gRNA library pools have been transduced into p53-null TVA-Cas9 neural stem cells (NSCs) and subsequently transplanted into NOD/SCID mice. So far, half of the mice rapidly developed (1–2 months) quite aggressive tumors. We are currently characterizing those tumors to identify the most potent oncogenic NTRK fusions. NTRK gene rearrangements are emerging as novel targets across multiple tumor types, because of the increasing availability of new drugs with anti-Trk activity. As part of our studies, we are investigating the response and the resistance mechanism to Trk inhibitors that are currently used in different clinical trials.