Sina Neyazi: Avapritinib as a novel targeted treatment for pediatric high-grade glioma with PDGFRA alterations
Sina Neyazi, Postdoctoral Research Fellow at
“I am thrilled to announce that our collaborative work with Mariella Filbin, Johannes Gojo and Carl Koschmann has been published in Cancer Cell by Cell Press!
In this study, we present a translational approach identifying the PDGFRA inhibitor avapritinib as a novel targeted treatment for pediatric high-grade glioma (pHGG) with PDGFRA alterations.
Key Highlights:
- We detected PDGFRA activating mutations and/or gene amplifications in ~15% of pHGG cases, with high-level amplifications often found on extrachromosomal DNA.
- Among various TKIs, the FDA-approved avapritinib showed remarkable selectivity against PDGFRA and high efficacy in PDGFRA-altered pHGG and DMG patient-derived models in vitro.
- Oral avapritinib demonstrated efficient brain penetrance and significantly prolonged survival in three PDGFRA-altered DMG models.
- Through wonderful clinical collaborations around the globe, we treated eight pediatric and young adult pHGG patients with avapritinib as a compassionate use and report first safety and response data in this patient population.
- Our early data demonstrate that avapritinib monotherapy is well tolerated and results in radiographic response in 3/7 cases, with best responses observed in patients with tumors harboring PDGFRA amplification or exon 18 mutation.
- We identified alternative receptor tyrosine kinase (RTK) pathway upregulation, such as novel EGFR amplification, as potential resistance mechanisms to avapritinib.
Implications: Our findings underscore the therapeutic potential of PDGFRA inhibition with avapritinib in pHGG and DMG patients with specific PDGFRA alterations—a patient group that currently faces a poor prognosis. We envision that molecularly targeted and personalized treatments like avapritinib, complemented by approaches such as CAR-T cells and ONC201, will lead the way in developing effective therapies for these aggressive cancers.
This achievement is the result of an incredible team effort. Special thanks to my co-first authors Lisa Mayr, Maria Trissal and Kallen Schwark for this immense team effort. I am deeply grateful to our collaborators across Dana-Farber Cancer Institute, Boston Children’s Hospital, University of Michigan, and MedUni Wien.
A heartfelt thank you to everyone Mariella Filbin for her exceptional mentorship, guidance, and support, and to all our collaborators and supporters who contributed to this journey.
Our deepest gratitude goes to the patients and families who trusted us with their care and provided invaluable tumor samples. We will keep fighting for better therapies for you!
This work was made possible by the generous support from Alex’s Lemonade Stand Foundation, The Sontag Foundation, The National Institutes of Health, ChadTough Defeat DIPG Foundation Pediatric Brain Tumor Foundation, Yuvaan Tiwari Foundation, and many more. Thank you for your essential contributions!”
Effective targeting of PDGFRA-altered high-grade glioma with avapritinib.
Authors: Lisa Mayr, et al.
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