Journal Club

Cancer Cell Volume 43, Issue 4, 14 April 2025, Pages 740-756.e8

Summary

PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.

Highlights

Avapritinib effectively and selectively inhibits PDGFRA signaling in gliomas
Avapritinib shows CNS penetrance and efficacy in pediatric high-grade glioma model
Safety profile of avapritinib is favorable in pediatric high-grade glioma patients
A subset of patients with PDGFRA-altered HGG shows clinical response to avapritinib