Effective targeting of high quality pediatric gliomas offers new hope

High-grade glioma in childrenespecially H3K27M Diffuse normal glioma (DMG)an aggressive malignant brain tumor with a poor prognosis. Previous studies suggest that platelet-derived growth factor receptor alpha (PDGFRA) appears to play a multifaceted role in both adult and pediatric pathogenesis. Not only is PDGFRA genetic alterations common in children with high-grade glioma, but elevated PDGFRA expression has been shown to be key to promoting DMG tumor growth.

Key takeout

• Changes in PDGFRA are relatively common in children with high-grade glioma patients and are potential therapeutic targets.
• The PDGFRA inhibitor avapritinib appears to be safe and tolerated in these patients.
• Early clinical data suggest that Avapritinib may prolong survival time in a subset of pediatric high-grade glioma patients with altered PDGFRA.

Currently led by the results of a recent multicenter study. Mariella Filbin, MD, PhDco-director of Brain Tumor Center Boston Children's Hospital and Dana-Farber Cancer Institute, PDGFRA may be a potential therapeutic target for high-grade gliomas in children. Filbin and her team, including collaborators from the University of Michigan School of Medicine and the Vienna University of Medicine, will also provide the first real-world clinical data to support the use of PDGFRA inhibitors in the treatment of high-grade glioma patients.

Identify potential treatment goals

To determine the frequency of PDGFRA changes in children's high-grade gliomas, Filbin and her colleagues analyzed genomic data from 217 advanced high-grade glioma samples in children. They identified changes in PDGFRA in nearly 15% of patients. Using transcriptome data, it was also discovered that PDGFRA expression was significantly increased in tumors with PDGFRA mutations 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 altered PDGFRA. Of these drugs, avapritinib was the highest potency. Additional preclinical tests also found avapritinib to have the lowest amount of target-off kinase activity, suggesting that the drug is less likely to cause unintended side effects.

Promising early clinical data

Finally, following additional testing in the mouse model, the researchers treated eight pediatric and young adult patients with high-quality gliomas along with avapritinib through a compassionate use program. Most patients had DMG, and seven out of eight had PDGFRA changes. All had previously undergone surgical biopsies or resections and radiation, so the four also had undergone chemotherapy or other treatment approaches.

Three patients responded to radiographic responses after being treated once daily with avapritinib for an average of four months. This drug was also tolerated. These three patients also survived, although they eventually metastasized, almost twice as many patients who did not respond to avapritinib.

This early data suggests that avapritinib is generally safe and may cause early clinical responses in small groups of patients with pediatric high-grade glioma with PDGFRA amplification.

“Our research currently provides the basis for clinical trials of avapritinib in newly diagnosed pediatric patients,” says Filbin. “Our follow-up work focuses on genetic markers for personalized therapies and develops combination therapies with FDA approved drugs to increase their efficacy.”

Please see more details on Brain Tumor Center Or refer the patient.

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