Platelet-derived growth factor receptor alpha (PDGFRA) is a potential new drug target for pediatric high-grade gliomas, according to research from Dana Farber and collaborators. The team also provided the first real-world clinical data to support the use of a PDGFRA inhibitor in the treatment of certain pediatric patients with high-grade gliomas.
The research was published in Cancer Cell, and the lead author is Dana Farber’s Lisa Mayer, MD. The senior author is Mariella Filbin, MD, PhD, co-director of the Brain Tumor Center at Boston Children’s Hospital and Dana-Farber Cancer Institute. The team included collaborators at the University of Michigan Medical School and the Medical University of Vienna.
This news comes soon after the first drug was approved in decades for low-grade glioma, which suggests some progress may be occurring against these hard-to-treat tumors. That drug, vorasidenib (Servier Pharmaceuticals’ Voranigo), is an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor.
Pediatric high-grade gliomas, particularly H3K27M diffuse midline gliomas (DMG), are aggressive malignant brain tumors with a poor prognosis. Previous research suggests that PDGFRA appears to play a role in both adult and pediatric high-grade gliomas. Genetic alterations of PDGFRA are common in patients with pediatric high-grade gliomas, and elevated PDGFRA expression has been shown to be key in driving the growth of DMG tumors.
Filbin and her colleagues analyzed genomic data from 217 pediatric high-grade glioma samples. They identified PDGFRA alterations in nearly 15% of patients. They also found significantly elevated PDGFRA expression in tumors with PDGFRA mutation or amplification.
Next, the team tested the activity of four PDGFRA inhibitors (dasatinib, crenolanib, axitinib, and avapritinib) against a panel of glioma cell lines with PDGFRA alterations. Of these drugs, avapritinib (Blueprint Medicines’ Ayvakit) exhibited the highest potency. Avapritinib was approved in 2023 as the first and only treatment for indolent systemic mastocytosis. In further studies by Filbin and her team, avapritinib also had the least amount of off-target kinase activity, suggesting it is less likely to cause unintended side effects.
Following additional testing, the researchers treated eight pediatric and young adult high-grade glioma patients with avapritinib through a compassionate use program. Most of the patients had DMGs, and seven of the eight had PDGFRA alterations. All had previously undergone surgical biopsy or resection and radiation, and four had also received chemotherapy or other treatment approaches.
After being treated with avapritinib once daily for an average of four months, three of the patients demonstrated a radiographic response. The drug was also well tolerated. These three patients also survived roughly twice as long as those who didn’t respond to avapritinib, although their disease ultimately metastasized.
This early data suggests that avapritinib is generally safe and may trigger an initial clinical response in a small group of patients who have pediatric high-grade gliomas with PDGFRA amplification.
“Our research now provides the basis for a clinical trial for avapritinib in newly diagnosed pediatric patients,” said Filbin. “Our follow-up work focuses on genetic markers for personalized treatment and developing combination therapies with FDA-approved drugs to enhance efficacy.”
