Developing new medications is a complex and time-consuming process—one that many patients with aggressive conditions cannot afford to wait for. An alternative strategy is to test existing drugs for new uses beyond their initial indication. This is not a novel concept; drugs have been repurposed from their original indications for decades.1 Because these drugs have already been approved by the FDA, repurposing them can fast-track safe and effective treatments to the patients who need them the most.
A recent study published in Cancer Cell exemplifies a successful repurposing approach in a patient population with historically poor outcomes: high-grade gliomas (HGGs).2 These aggressive, fast-growing brain tumors—particularly devastating in children—have low survival rates and limited treatment options.3,4
Mariella Filbin, a pediatric neuro-oncologist and researcher at Dana-Farber Cancer Institute and coauthor of this study, has been trying to find new treatment options for her patients. When she and her team started looking for a potential target they turned their attention to platelet-derived growth factor receptor alpha (PDGFRA), which is commonly mutated in pediatric HGGs.5 Further supporting the gene’s role in cancer, researchers alter PDGFRA in rodents to drive tumor development.6 Using genomic sequencing data from pediatric patients with HGGs, the researchers found that a subset had more copies of PDGFRA. Furthermore, the patients’ cancerous cells had more copies of the gene than noncancerous cells. “This all made us think that we really have to get [PDGFRA] inhibitors into in vitro and in vivo experiments and see what happens,” said Filbin.
Filbin and her team searched for drugs that were already approved or currently being investigated by the FDA and known PDFGRA inhibitors. They found four such drugs and tested them using both mouse HGG and patient-derived cell lines to investigate which most strongly altered PDGFRA expression and signaling. A drug called avapritinib, used to treat gastrointestinal stromal tumors with PDGFRA mutations, showed the greatest potency, evidenced by reduced expression of phosphorylated PDGFRA and increased cell death via apoptosis.7
For avapritinib to be effective against HGGs, it would need to show that it is capable of crossing into the brain. “The challenge has been finding drugs that are specific and potent enough, and get through the blood-brain barrier,” said Oren Becher, a pediatric oncologist at Mount Sinai Kravis who was not involved in the study. When Filbin’s team tested avapritinib in an animal model of HGG, they found that the drug penetrated the brain and decreased tumor growth. These findings motivated the study team to expand the research to human patients.
Coincidentally, avapritinib was practically next door. “It just so happens that this drug is made by a company here in Boston that’s across the river,” said Filbin. Blueprint Medicines offers a compassionate use program that provides patients with life-threatening conditions access to investigational drugs or off-label uses when no approved or effective treatments are available. Filbin’s group teamed-up with Blueprint Medicines, Johannes Gojo at the Medical University of Vienna, and Carl Koschmann at the University of Michigan Medical School to test avapritinib in eight patients, aged four to 29 years, with challenging and highly treatment-refractory HGGs. Seven of the patients’ tumors had confirmed PDGFRA alterations. Avapritinib was generally well-tolerated and safe, and radiographic assessments showed changes in tumor shape and size in three patients, who also demonstrated prolonged survival.
Although the study included a small number of cases, the results indicate a potential new treatment for HGGs, particularly in patients with PDGFRA mutations. Notably, these patients had already undergone extensive treatment with other pharmacological, surgical, and chemotherapeutic interventions. “That’s a very tough population to treat, in a disease where everybody dies within nine to 12 months,” said Filbin, “While this is very hopeful and we are super excited, we need a clinical trial that really proves or disproves that our initial findings are correct.” Filbin’s team hopes to design a clinical trial for newly diagnosed patients who have PDGFRA mutations.
“[These findings] suggest that single drugs are never ‘home-runs’ in these high-grade gliomas, but this sets the stage for future combination studies to find something that will synergize with avapritinib to enhance efficacy,” noted Becher. Filbin’s team will continue preclinical research to expand their understanding of avapritinib in HGGs and produce other avenues for bench-to-bedside interventions. Filbin added, “We are also aware that a single drug in a very, very aggressive disease that can evolve quickly will not be enough to do what we want, which is to have long term survivors.” Her lab is currently pursuing preclinical combination trials investigating which other drugs or therapies could be combined with avapritinib to have longer lasting and more profound effects for these patients.
- Jourdan JP, et al. Drug repositioning: A brief overview. J Pharm Pharmacol. 2020;72(9):1145-1151.
- Mayr L, et al. Effective targeting of PDGFRA-altered high-grade glioma with avapritinib. Cancer Cell. 2025;43(4):740-756.e8.
- Jones C, et al. Pediatric high-grade glioma: Biologically and clinically in need of new thinking. Neuro Oncol. 2017;19(2):153-161.
- Ostrom QT, et al. CBTRUS statistical report: Pediatric brain tumor foundation childhood and adolescent primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro Oncol. 2022;24(Suppl 3):iii1-iii38.
- Paugh BS, et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res. 2013;73(20):6219-6229.
- Pathania M, et al. H3.3K27M cooperates with Trp53 loss and PDGFRA gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas. Cancer Cell. 2017;32(5):684-700.e9.
- Kang YK, et al. Avapritinib versus regorafenib in locally advanced unresectable or metastatic GI stromal tumor: A randomized, open-label phase III study. J Clin Oncol. 2021;39(28):3128-3139.
