TRLS-13. NOVEL PAN-RAF INHIBITOR BELVARAFENIB AS A PROMISING TARGETED THERAPY FOR BRAF-ALTERED PEDIATRIC LOW-GRADE GLIOMAS

In recent years targeted therapy has improved the outcome of childhood cancer patients. The second most common pediatric cancers are central nervous system (CNS) tumors, particularly low-grade gliomas (LGGs). Approximately 15-20% of pediatric LGGs cases present with oncogenic mutations that alter the RAS/mitogen-activated protein kinase (MAPK) signaling pathway by the B-RAF kinase constitutive activation. Only five RAF inhibitors are FDA-approved as cancer treatments and with limited-to-no data for pediatric patients. The lack of pediatric data results from limited access to childhood clinical trials, although there has been an increase in clinical trials for RAF inhibitors and combinations for children. However, there is a pressing need for alternative therapeutic approaches for pediatric patients with BRAF-altered LGGs. Hence, this study proposes a type II pan-RAF inhibitor called Belvarafenib (BEV) as a potential therapeutic candidate. Belvarafenib has shown viability effects at 500fM to 5nM in a PRKAR2B/BRAF fusion patient-derived cell line with a calculated cytotoxic concentration 50 (CC(50)) of 2nM. The expression of apoptotic markers will be measured to characterize the mechanism of cell death through BEV’s direct stimulation of the MAPK signaling or via an alternative pathway. Understanding the allosteric properties of the RAF inhibitor Belvarafenib enables the opportunity to have effective and well-tolerated alternative therapies for BRAF-altered tumors in children. Thus, this preliminary study intends to profile the effectivity of Belvarafenib in cell culture and help design in vivo experiments with the potential to establish clinical trials in combination with other potential therapeutic agents.