Novel Therapy Targets Pediatric Brain Tumors

Brain tumors continue to be the leading cause of childhood cancer-related deaths. Among these, pediatric high-grade gliomas (pHGG) are particularly aggressive, with most cases being fatal and a median survival of under 18 months post-diagnosis, alongside few effective treatments. () A collaborative research team from MedUni Vienna/University Hospital Vienna, the Dana-Farber Cancer Institute, and the University of Michigan Medical School has identified Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) as a potential therapeutic target. Their findings were recently published in the journal Cancer Cell.

Conquering Childhood Brain Tumors: Targeting Aggressive Gliomas

Brain tumours are the most common type of cancer in children and adolescents and are the main cause of cancer-related deaths in this age group. Paediatric high-grade gliomas (pHGG) are a particularly aggressive type of tumour 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 signalling pathway by a specific selective PDGFRA inhibitor is a potential therapeutic approach for this aggressive brain tumour type.

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," says study leader Johannes Gojo.

Furthermore, initial clinical experience with avapritinib therapy in paediatric 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. "Tumours 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 paediatric 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.

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Reference:

1. Effective targeting of PDGFRA-altered high-grade glioma with avapritinib - (https://www.sciencedirect.com/science/article/pii/S1535610825000704?via%3Dihub)

Source-Eurekalert