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

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

A study, published in Cancer Cell, shows that high-grade glioma tumor cells harboring DNA alterations in the gene PDGFRA responded to the drug avapritinib, which is already approved by the United States Food and Drug Administration to treat gastrointestinal stromal tumors with a PDGFRA exon 18 mutation as well advanced systemic mastocytosis and indolent systemic mastocytosis.

“We were excited to see that avapritinib essentially shut off PDGFRA signaling in mouse brain tumors,” said Carl Koschmann, M.D., ChadTough Defeat DIPG Research Professor and clinical scientific director of the Chad Carr Pediatric Brain Tumor Center at C.S. Mott Children’s Hospital.

Aside from surgery and radiation, there aren’t effective drugs to treat high-grade gliomas, especially upon recurrence. Koschmann and his collaborators targeted PDGFRA, which is one of the most commonly mutated genes, as a potential inroad to discover new drug therapies.

"We'd been doing screens with a lot of commercially available drugs that inhibit PDGFRA. We found avapritinib to be the strongest and most focused inhibitor that targets PDGFRA alterations,” Koschmann said.

Along with colleagues from the labs of Mariella Filbin MD, PhD (Dana Farber Cancer Institute) and Johannes Gojo (Medical University of Vienna) who were investigating the effectiveness of PDGFRA inhibitors, Koschmann and his team were excited to see that avapritinib crosses the blood brain barrier, a normally high hurdle for drugs.

"When we gave mice the drug and showed that it reached the brain, we knew we were onto something,” explained Kallen Schwark, a U-M M.D./Ph.D. student and one of the study’s lead authors.

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

“Across multiple international institutions, we treated the first eight patients with high-grade glioma with avapritinib,” Koschmann explained. 

“The patients tolerated the drug well and in three of the eight patients, we were able to see their tumors shrink.”  

This early data and preclinical data helped provide the basis to include pediatric high-grade glioma in a phase I pediatric solid tumor trial, which recently completed accrual, and for which analysis is underway.

“We have very few examples of drugs entering brain tumors like this and shutting down key oncogenic pathways. These results support a lot of ongoing efforts to build on the success of avapritinib and other brain penetrant small molecule inhibitors,” Koschmann continued.

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

“We know a single drug is not going to be enough for this disease,” he said. 

“The way to make true progress will be combining many different types of modalities, like combining drugs that are target pathways activated by the first drug. We already have a follow-up story on targeting avapritinib with MAP kinase inhibitors that we are just as excited about.”

 Additional authors: Mayr Lisa, Neyazi Sina, Schwark Kallen, Trissal Maria, Beck Alexander, Labelle Jenna, Eder Sebastian K, Weiler-Wichtl Liesa, Marques Joana G, de Biagi-Junior Carlos AO, Lo Cascio Costanza, Chapman Owen, Sridhar Sunita, Kenkre Rishaan, Dutta Aditi, Wang Shanqing, Wang Jessica, Hack Olivia, Nascimento Andrezza, Nguyen Cuong M, Castellani Sophia, Rozowsky Jacob S, Groves Andrew, Panditharatna Eshini, Alencastro Veiga Cruzeiro Gustavo, Haase Rebecca D, Tabatabai Kuscha, Madlener Sibylle, Wadden Jack, Adam Tiffany, Kong Seongbae, Miclea Madeline, Patel Tirth, Bruckner Katharina, Senfter Daniel, Lammerer Anna, Supko Jeffrey, Guntner Armin S, Palova Hana, Neradil Jakub, Stepien Natalia, Lotsch-Gojo Daniela, Berger Walter, Leiss Ulrike, Rosenmayr Verena, Dorfer Christian, Dieckmann Karin, Peyrl Andreas, Azizi Amedeo A, Baumgartner Alicia, Slaby Ondrej, Pokorna Petra, Clark Louise M, Cameron Amy, Nguyen Quang-De, Wakimoto Hiroaki, Dubois Frank, Greenwald Noah F, Bandopadhayay Pratiti, Beroukhim Rameen, Ligon Keith, Kramm Christof, Bronsema Annika, Bailey Simon, Guerreiro Stucklin Ana, Mueller Sabine, Skrypek Mary, Martinez Nina, Bowers Daniel C, Jones David TW, Jones Chris, Jager Natalie, Sterba Jaroslav, Mullauer Leonhard, Haberler Christine, Kumar-Sinha Chandan, Chinnaiyan Arul, Mody Rajen, Chavez Lukas, Furtner Julia, Koschmann Carl, Gojo Johannes and Filbin Mariella.

Funding/disclosures: This work was supported by Sajni Chakrabarti Fund for Pediatric Brain Cancer Research, Caroline Mortimer Fund, Claudia Adams Barr Program, Cuming Family Fund for Pediatric Brain Tumor Research, Anita, Sophia, and Athena Fund to Advance DIPG Research and Care, Liv Like A Unicorn, We love you Connie Fund and the DIPG All-In Initiative.

Filbin holds a NIH director’s New Innovator award (DP2NS127705), a Career Award for Medical Scientist from the Burroughs Wellcome Fund, the Distinguished Scientist Award from the Sontag Foundation, the Helen Gurley Brown Foundation Helen Gurley Brown Presidential Initiative at Dana-Farber Cancer Institute and the A-Award from the Alex’s Lemonade Stand Foundation. Filbin was also supported by National Cancer Institute SPORE grant 684 2P50CA165962 and by National Cancer Institute U54 grant CA274516. Koschmann was supported by National Institutes of Health Grant R01-NS119231 and R01-NS124607, DOD Grant CA201129P1, University of Michigan Chad Carr Pediatric Brain Tumor Center, Evans Family, ChadTough Defeat DIPG Foundation, Catching Up with Jack, Pediatric Brain Tumor Foundation, Michael Miller Memorial Foundation, Morgan Behen Golf Classic and Yuvaan Tiwari Foundation. Gojo was supported by Forschungsgesellschaft fuer cerebrale Tumore and Verein unser_kind. Jones was supported by Cancer Research UK, CRIS Cancer Foundation and Brain Tumour Research.

Other funding sources were Physician Researcher Pathway Scholarship of the Medical University of Vienna, the Medical-scientific fund of the Mayor of the federal capital Vienna (project #19086), the Austrian Science fund (project T906-B28 and P30105), Ministry of Health of the Czech Republic (NU20-03-00240) and Walter Benjamin Programme of the German Research Foundation.

Conflict(s) of interest: Filbin was a consultant for Redona Therapeutics (previously named Twentyeight-Seven, Inc.) and Blueprint Medicines Corporation.

Paper cited: “Effective targeting of PDGFRA-altered high-grade 1 glioma with avapritinib,” Cancer Cell. DOI: 10.1016/j.ccell.2025.02.018

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