TMOD-07. NTRK3 GENE FUSIONS DRIVE TUMORIGENESIS IN NOVEL MODELS OF PEDIATRIC HIGH GRADE GLIOMA

摘要

A greater understanding of the unique drivers of pediatric high-grade gliomas (pHGG) is needed as the two-year survival rate is only 10–30%. We recently discovered the presence of structural variants in 47% of pHGG. Recurrent fusions were found involving neurotrophin receptors (NTRK) in 7% of all pHGG and 40% of non-brainstem HGG in infants. One chimeric gene we identified encoded the ETS transcription factor, ETV6, fused to the kinase domain of NTRK3 causing ligand-independent kinase activity. ETV6-NTRK3 has been identified in other neoplasms including congenital-infantile fibrosarcoma and AML. To examine the role of ETV6-NTRK3 in glioma formation in vivo, we developed an implantation model. Cortical astrocytes with conditional loss of p53 in neural stem cells were harvested from mice at P2, transduced with a vector expressing ETV6-NTRK3, and were implanted into the cortex of adult mice. Even with a transduction efficiency of only 1.5–2%, all mice implanted with transduced astrocytes developed HGG with a median survival of 36 days. Next, to study ETV6-NTRK3 in the development of pediatric gliomas, we generated a spontaneous tumor model in which mice expressed a conditional knock-in ETV6-NTRK3 allele and conditional loss of p53 in primitive neural stem cells. Mice expressing ETV6-NTRK3 and null p53 showed rapid development and complete penetrance of high-grade glioma with a median survival of 18 days. Evidence of HGG development was readily detectable by P5, accurately recapitulating onset of pediatric gliomagenesis. Analysis showed ETV6-NTRK3 primary astrocytes had increased proliferation compared to control astrocytes and HGGs driven by ETV6-NTRK3 showed a high proliferative index, MAPK, PI3K and PLCγ activity. In vitro and in vivo models were employed to identify oncogenic targets downstream of NTRK fusions and for preclinical testing of TRK selective inhibitors.