New therapeutic approach shows promise for pediatric high-grade gliomas

Brain tumors remain the most common cause of death from childhood cancer. Paediatric high-grade gliomas (pHGG) in particular are a mostly fatal disease group with a median survival time of less than 18 months after diagnosis and limited treatment options. A research team from MedUni Vienna/University Hospital Vienna, the Dana-Farber Cancer Institute and the University of Michigan Medical School identified Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) as a promising therapeutic approach. The study has just been published in the scientific journal "Cancer Cell".

Brain tumors are the most common type of cancer in children and adolescents and are the main cause of cancer-related deaths in this age group. Pediatric high-grade gliomas (pHGG) are a particularly aggressive type of tumor that cannot be cured in most cases today. Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) plays a role at multiple levels in the development of high-grade gliomas and represents a promising therapeutic target. Previous attempts to block PDGFRA in pHGG have been clinically unsuccessful, likely due to poor tolerability and lack of penetration into the central nervous system (CNS). The current research led by Johannes Gojo (Department of Pediatrics and Adolescent Medicine), Mariella Filbin (Dana-Farber Cancer Institute) and Carl Koschmann (University of Michigan Medical School) has shown that inhibition of the PDFGRA signaling pathway by a specific selective PDGFRA inhibitor is a potential therapeutic approach for this aggressive brain tumor type.

Blocking the PDGFRA signaling pathway leads to tumor cell death

In a comprehensive analysis of pediatric HGG cases, PDGFRA mutations and/or amplifications were identified in 15% of cases, identifying PDGFRA alterations as one of the most frequent genetic aberrations in pediatric high-grade gliomas and suggesting it as a potential target for therapy. The international collaboration was able to show that the inhibitor avapritinib specifically and selectively inhibits PDGFRA, works in both laboratory and animal models of high-grade gliomas and effectively crosses the blood-brain barrier in mice and humans.

The PDGFRA changes in high-grade gliomas lead to increased aggressiveness and growth, but at the same time create a target for effective therapeutic strategies."

Johannes Gojo, study leader

Furthermore, initial clinical experience with avapritinib therapy in pediatric and young adult patients with predominantly relapsed/refractory PDGFRA-altered HGG has shown that avapritinib is well tolerated and has achieved a radiological response in 3 out of 7 cases. "tumors with specific PDGFRA alterations that were previously resistant to standard radiotherapy have responded to this new therapeutic approach. Our findings provided the basis for an international phase 1/2 clinical trial and the basis for further combination trials of avapritinib in pediatric high-grade gliomas with PDGFRA alterations," adds first author Lisa Mayr.

These clinically highly relevant findings were the result of a collaboration between several different disciplines at the Comprehensive Cancer Centre of MedUni Vienna and University Hospital Vienna, as well as national and international collaboration partners.