Development of KIAA1549-BRAF Fusion Inhibitors and Brain-Penetrant Pan-BRAF Inhibitors

National Center For Advancing Translational Sciences

Investigators

Abstract

Pediatric low-grade glioma (pLGG) is the most common CNS tumor in children. The primary treatment for pLGG is surgical resection, but this is not possible when the tumor resides in sensitive brain structures. Recent advances in molecular diagnostics have revealed that the mitogen-activated protein kinase (MAPK) pathway is a key driver of pLGG tumorigenesis. The most common driver mutations that activate this pathway occur in the serine/threonine-protein kinase BRAF; the KIAA1549-BRAF (16:9) fusion and the BRAF V600E mutation account for 68% and 62% of all pLGG gene rearrangement and SNV driver mutations, respectively. We will endeavor to develop brain-penetrant small molecule therapeutics that target this pathway.