One of the leading causes of cancer-related death in childhood is brain tumors, especially pediatric high-grade gliomas, which include H3K27M diffuse midline gliomas (DMGs), which are highly fatal with a median survival of <18 months.1 On multiple levels, platelet-derived growth factor receptor alpha (PDGFRA) is responsible for the pathogenesis of high-grade glioma, with genomic alterations commonly detected in pHCG and adult glioblastoma (GBM).2
The Brain Tumor Center at Boston Children’s Hospital and Dana-Farber Cancer Institute conducted a multicentric study that proposed that for pediatric high-grade gliomas, the PDGFRA can be a prospective therapeutic target. Filbin and her team, along with partners from the University of Michigan Medical School and the Medical University of Vienna, presented the first clinical data from real-world settings that support the use of a PDGFRA inhibitor in treating specific pediatric patients with high-grade gliomas. They analyzed genomic data from 217 pediatric high-grade glioma samples to ascertain the PDGFRA alterations frequency. In nearly 15% of patients, PDGFRA alterations were identified, and by using the transcriptomic data, they discovered that PDGFRA expression was increased significantly in tumors with PDGFRA mutation or amplification. Apart from this, the team also tested the activity of four PDGFRA inhibitors (Dasatinib, Crenolanib, Axitinib and Avapritinib) on glioma cell lines with PDGFRA alterations, amongst which Avapritinib showed highest potency. Also, Avapritinib had minimal off-target kinase activity reducing unwanted side effects of the drugs.3
About eight pediatric patients and young adults with high-grade gliomas, most of them having DMGS, and seven of the eight patients had PDGFRA alterations, were treated with avapritinib. All of them also had undergone surgical biopsy or resection and radiation, and four of them had undergone chemotherapy or other treatment. Treating these patients with avapritinib once a day for about 4 months, three of them showed radiographic response, and the drug was well tolerated by all. These three patients survived twice as long as those who did not respond to avapritinib, but ultimately, they also developed metastasis.
Preliminary data indicate that avapritinib is generally well-tolerated and may lead to an initial clinical response in a small subset of patients with paediatric high-grade gliomas characterized by PDGFRA amplification.4 Filbin explains, "Our findings now lay the groundwork for a clinical trial of avapritinib in newly diagnosed paediatric patients. Moving forward, we will focus on identifying genetic markers for personalized treatment and exploring combination therapies with FDA-approved medications to improve efficacy”.
Reference:
- Kaatsch P. Epidemiology of childhood cancer. Cancer treatment reviews. 2010 Jun 1;36(4):277-85.
- Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, Bjerke L, Clarke M, Vinci M, Nandhabalan M, Temelso S. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer cell. 2017 Oct 9;32(4):520-37.
- Heinrich MC, Jones RL, von Mehren M, Schöffski P, Serrano C, Kang YK, Cassier PA, Mir O, Eskens F, Tap WD, Rutkowski P. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. The Lancet Oncology. 2020 Jul 1;21(7):935-46.
- Lisa Mayr et al, Effective targeting of PDGFRA-altered high-grade glioma with avapritinib, Cancer Cell (2025). DOI: 10.1016/j.ccell.2025.02.018
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