Analysis of avapritinib efficacy in combinatorial drug therapy for PDGFRA-driven pediatric high grade glioma (pHGG)
Mentor Name: Carl Koschmann
Advancing research in neuro-oncology is urgently needed, as only 10% of patients with high-grade gliomas survive past 2 years. With no effective treatments, the field has turned to targeted therapy as a potential avenue for improving patient outcomes. Our project aims to characterize the synergistic performance of the drug avapritinib in combinatorial drug settings as a targeted therapy for pediatric high-grade glioma (pHGG). One of the most commonly altered genes in pHGG is PDGFRA--a tyrosine kinase receptor that is amplified or mutated in roughly one-fifth of pHGG cases. Avapritinib is a new inhibitor that has been shown to target PDGFRA effectively, have few off-target effects, and cross the blood-brain barrier. There is a lack of pre-clinical data and studies regarding avapritinib’s efficacy, leading us to develop the foundation for this project. This past year, we were able to analyze avapritinib amongst a myriad of PDGFRA mutants by using specialized mouse models and laboratory techniques. Through this specialized research, we were able to understand avapritinib’s mechanistic scope, which has led us to question its ability in conjunction with other targeted drug therapies. Our hypothesis is that avapritinib displays synergistic ability in combinatorial drug therapy to target mutant PDGFRA more effectively due to its design against the mutant protein and its high brain penetration.
