Characterization and Targeting of Novel Activating BRAF Mutations in Pediatric Brain Tumors
Low-grade glioma is one of the most common types of brain tumor that occur in children. Until recently, little was known about the molecular events that led to glioma formation. As a direct result of this paucity of information, low-grade glioma directed treatment has significantly lagged behind advances made in other childhood malignancies. Children with unresectable or recurrent/disseminated low-grade gliomas have been left with few treatment options. Their event free and overall survival rates have been dismal. Our discovery of an activated novel KIAA1549-BRAF fusion oncogene in the majority of pediatric low-grade gliomas is a breakthrough that opens the doorway for insights in tumorigenesis and new treatment options. We propose that further investigation of the oncogenic addiction of the RAS/RAF/MEK pathway, and specifically of the KIAA1549-BRAF fusion, will provide a better understanding of the molecular events that drive low-grade gliomas. Mechanistic studies will test whether KIAA1549-BRAF dysregulates the MAPK pathway in the same manner as BRAF V600E. Preclinical in vivo and in vivo testing will show whether activated BRAF specific inhibitors already in clinical development will be effective in tumors harboring the KIAA1549-BRAF fusion. Ultimately, we hope to find new cures for children with low-grade gliomas.