Already approved drug Avapritinib shows promise in treating high-grade gliomas

Already approved drug Avapritinib shows promise in treating high-grade gliomas

High-grade glioma, an aggressive form of pediatric and adult brain cancer, is challenging to treat given tumor location, recurrence, and difficulty for drugs to cross the blood-brain barrier.

Researchers from the University of Michigan, the Dana Farber Cancer Institute and the Medical University of Vienna have established a collaborative team to uncover a potential new way to combat this disease.

A study published inCancer cellshows that high-grade glioma tumor cells contain DNA changes in the genePDGFRAresponded to the drug avapritinib, which is already approved by the US Food and Drug Administration for the treatment of gastrointestinal stromal tumors with a PDGFRA exon 18 mutation as well as well-advanced systemic mastocytosis and indolent systemic mastocytosis.

We were excited to see that avapritinib essentially eliminated PDGFRA signaling in mouse brain tumors. “

Carl Koschmann, MD, Chadtough Defeat DIPG Research Professor and Clinical Scientific Director of the Chad Carr Pediatric Brain Tumor Center at CS Mott Children's Hospital

Aside from surgery and radiation, there are no effective medications to treat high-grade gliomas, especially in readmissions. Koschmann and his employees took aimPDGFRAwhich is one of the most commonly mutated genes, as a potential introduction to discover new drug therapies.

“We had made screens with many commercially available drugs that inhibitPDGFRA. We found that avapritinib is the most potent and focused inhibitor to targetPDGFRAChanges,” said Koschmann.

Along with colleagues from the laboratories of Mariella Filbin MD, PhD (Dana Farber Cancer Institute) and Johannes Gojo (Medical University of Vienna) studying the effectiveness of PDGFRA inhibitors, Koschmann and his team were excited to see that avapritinib crosses the blood brain barrier, a normally high hurdle, the normal hurdle caused by drug abuse.

“When we gave mice the drug and showed that it reached the brain, we knew we were on to something,” explained Kallen Schwark, a UM MD/Ph.D. student and one of the lead authors of the study.

The team was able to treat some patients with high-grade glioma through an expanded access program set up by Blueprint while a clinical trial was not yet available.

“We treated the first eight patients with high-grade glioma with avapritinib in several international institutions,” explained Koschmann.

“The patients tolerated the drug fountain and three of the eight patients were able to shrink their tumors.”

These early data and preclinical data provided the basis for pediatric high-grade glioma in a recently completed Phase I pediatric tumor study, for which analysis is ongoing.

"We have very few examples of drugs that enter such brain tumors and knock down key oncogenic pathways. These results support many ongoing efforts to build on the success of avapritinib and other small molecule inhibitors in brain penetration," Koschmann continued.

High-grade gliomas are very aggressive, with a prognosis of less than two years and limited treatment options. Although this work is preliminary, Koschmann hopes that avapritinib could be an additional tool to help patients.

“We know that a single drug will not be enough for this disease,” he said.

"The way to make real progress will be to combine many different types of modalities, such as combining drugs that are target pathways activated by the first drug. We already have a follow-up story on avapritinib with MAP kinase inhibitors that we are equally excited about."

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