Effective targeting of PDGFRA-altered high-grade glioma with avapritinib

Lisa Mayr¹, Sina Neyazi², Kallen Schwark³, Maria Trissal², Alexander Beck⁴, Jenna Labelle², Sebastian K Eder⁵, Liesa Weiler-Wichtl⁶, Joana G Marques², Carlos A O de Biagi-Junior², Costanza Lo Cascio², Owen Chapman⁷, Sunita Sridhar⁷, Rishaan Kenkre⁷, Aditi Dutta⁷, Shanqing Wang⁷, Jessica Wang⁷, Olivia Hack², Andrezza Nascimento², Cuong M Nguyen², Sophia Castellani², Jacob S Rozowsky², Andrew Groves², Eshini Panditharatna², Gustavo Alencastro Veiga Cruzeiro², Rebecca D Haase², Kuscha Tabatabai², Sibylle Madlener⁶, Jack Wadden³, Tiffany Adam³, Seongbae Kong³, Madeline Miclea³, Tirth Patel³, Katharina Bruckner⁸, Daniel Senfter⁶, Anna Lämmerer⁹, Jeffrey Supko¹⁰, Armin S Guntner¹¹, Hana Palova¹², Jakub Neradil¹³, Natalia Stepien⁶, Daniela Lötsch-Gojo¹⁴, Walter Berger¹⁵, Ulrike Leiss⁶, Verena Rosenmayr⁶, Christian Dorfer¹⁴, Karin Dieckmann¹⁶, Andreas Peyrl⁶, Amedeo A Azizi⁶, Alicia Baumgartner¹, Ondrej Slaby¹⁷, Petra Pokorna¹², Louise M Clark¹⁸, Amy Cameron¹⁸, Quang-De Nguyen¹⁸, Hiroaki Wakimoto¹⁹, Frank Dubois², Noah F Greenwald²⁰, Pratiti Bandopadhayay², Rameen Beroukhim²¹, Keith Ligon², Christof Kramm²², Annika Bronsema²³, Simon Bailey²⁴, Ana Guerreiro Stucklin²⁵, Sabine Mueller²⁶, Mary Skrypek²⁷, Nina Martinez²⁸, Daniel C Bowers²⁹, David T W Jones³⁰, Chris Jones³¹, Natalie Jäger³², Jaroslav Sterba³³, Leonhard Müllauer³⁴, Christine Haberler³⁵, Chandan Kumar-Sinha³⁶, Arul Chinnaiyan³⁶, Rajen Mody³, Lukas Chavez⁷, Julia Furtner³⁷, Carl Koschmann³⁸, Johannes Gojo³⁹, Mariella G Filbin⁴⁰

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
² Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA.
³ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Center for Neuropathology and Prion Research, Ludwig Maximilians University Munich, Faculty of Medicine, Muenchen, 80539 Bayern, Germany.
⁵ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna and St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria.
⁶ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
⁷ Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA.
⁸ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Department of Neurosurgery, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
⁹ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, 1090 Vienna, Austria.
¹⁰ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Institute for Analytical and General Chemistry, Johannes Kepler University, 4040 Linz, Austria.
¹² Central European Institute of Technology, Masaryk University, 60177 Brno, Czech Republic.
¹³ Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
¹⁴ Department of Neurosurgery, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
¹⁵ Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, 1090 Vienna, Austria.
¹⁶ Department of Radiotherapy, Medical University of Vienna, 1090 Vienna, Austria.
¹⁷ Central European Institute of Technology, Masaryk University, 60177 Brno, Czech Republic; Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
¹⁸ Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
¹⁹ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02115, USA.
²¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
²² Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
²³ Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
²⁴ Great North Childrens Hospital and Newcastle University, Newcastle upon Tyne, UK; Newcastle Hospitals NHS Foundation Trust, NE1 4LP Newcastle, UK.
²⁵ Department of Oncology and Children's Research Center, University Children's Hospital Zurich, 8008 Zurich, Switzerland.
²⁶ Departments of Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
²⁷ Department of Pediatric Hematology-Oncology, Children's Minnesota, Minneapolis, MN 55404, USA.
²⁸ Department of Neurology & Neurological Surgery, Jefferson University, Philadelphia, PA 19107, USA.
²⁹ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³⁰ Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
³¹ Division of Molecular Pathology, Institute of Cancer Research, SM2 5NG London, UK.
³² Hopp Children's Cancer Center Heidelberg (KiTZ) & Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
³³ Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 662630 Brno, Czech Republic.
³⁴ Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
³⁵ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.
³⁶ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³⁷ Division of Neuroradiology and Musculoskeletal Radiology, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria; Research Center of Medical Image Analysis and Artificial Intelligence, Danube Private University, 3500 Krems an der Donau, Austria.
³⁸ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: ckoschma@med.umich.edu.
³⁹ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: johannes.gojo@meduniwien.ac.at.
⁴⁰ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mariella.filbin@childrens.harvard.edu.

PMID: 40086436
PMCID: PMC12121847 (available on 2026-04-14)
DOI: 10.1016/j.ccell.2025.02.018

Effective targeting of PDGFRA-altered high-grade glioma with avapritinib

Lisa Mayr et al. Cancer Cell. 2025.

. 2025 Apr 14;43(4):740-756.e8.

doi: 10.1016/j.ccell.2025.02.018. Epub 2025 Mar 13.

Authors

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
² Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA.
³ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Center for Neuropathology and Prion Research, Ludwig Maximilians University Munich, Faculty of Medicine, Muenchen, 80539 Bayern, Germany.
⁵ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna and St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria.
⁶ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
⁷ Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA.
⁸ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Department of Neurosurgery, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
⁹ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, 1090 Vienna, Austria.
¹⁰ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Institute for Analytical and General Chemistry, Johannes Kepler University, 4040 Linz, Austria.
¹² Central European Institute of Technology, Masaryk University, 60177 Brno, Czech Republic.
¹³ Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
¹⁴ Department of Neurosurgery, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
¹⁵ Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, 1090 Vienna, Austria.
¹⁶ Department of Radiotherapy, Medical University of Vienna, 1090 Vienna, Austria.
¹⁷ Central European Institute of Technology, Masaryk University, 60177 Brno, Czech Republic; Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
¹⁸ Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
¹⁹ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02115, USA.
²¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
²² Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany.
²³ Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
²⁴ Great North Childrens Hospital and Newcastle University, Newcastle upon Tyne, UK; Newcastle Hospitals NHS Foundation Trust, NE1 4LP Newcastle, UK.
²⁵ Department of Oncology and Children's Research Center, University Children's Hospital Zurich, 8008 Zurich, Switzerland.
²⁶ Departments of Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
²⁷ Department of Pediatric Hematology-Oncology, Children's Minnesota, Minneapolis, MN 55404, USA.
²⁸ Department of Neurology & Neurological Surgery, Jefferson University, Philadelphia, PA 19107, USA.
²⁹ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³⁰ Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
³¹ Division of Molecular Pathology, Institute of Cancer Research, SM2 5NG London, UK.
³² Hopp Children's Cancer Center Heidelberg (KiTZ) & Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
³³ Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 662630 Brno, Czech Republic.
³⁴ Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
³⁵ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.
³⁶ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³⁷ Division of Neuroradiology and Musculoskeletal Radiology, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria; Research Center of Medical Image Analysis and Artificial Intelligence, Danube Private University, 3500 Krems an der Donau, Austria.
³⁸ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: ckoschma@med.umich.edu.
³⁹ Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: johannes.gojo@meduniwien.ac.at.
⁴⁰ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mariella.filbin@childrens.harvard.edu.

PMID: 40086436
PMCID: PMC12121847 (available on 2026-04-14)
DOI: 10.1016/j.ccell.2025.02.018

Abstract

PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.

Keywords: PDGFRA alteration; PDGFRA amplification; PDGFRA inhibitor; PDGFRA mutation; avapritinib; brain penetrance; diffuse midline glioma; glioblastoma; high-grade glioma; tyrosine kinase inhibitor.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests Mariella G. Filbin was a consultant for Redona Therapeutics (previously named Twentyeight-Seven, Inc.) and Blueprint Medicines Corporation.

References

1. Kaatsch P. (2010). Epidemiology of childhood cancer. Cancer Treat Rev 36, 277–285. 10.1016/j.ctrv.2010.02.003. - DOI - PubMed
1. Pollack IF, Agnihotri S, and Broniscer A (2019). Childhood brain tumors: current management, biological insights, and future directions. J Neurosurg Pediatr 23, 261–273. 10.3171/2018.10.PEDS18377. - DOI - PMC - PubMed
1. Ostrom QT, Price M, Ryan K, Edelson J, Neff C, Cioffi G, Waite KA, Kruchko C, and Barnholtz-Sloan JS (2022). 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 24, iii1–iii38. 10.1093/neuonc/noac161. - DOI - PMC - PubMed
1. Organisation mondiale de la santé and Centre international de recherche sur le cancer eds. (2021). Central nervous system tumours 5th ed. (International agency for research on cancer; ).
1. Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, Bjerke L, Clarke M, Vinci M, Nandhabalan M, et al. (2017). Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell 32, 520–537.e5. 10.1016/j.ccell.2017.08.017. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

DP2 NS127705/NS/NINDS NIH HHS/United States

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Effective targeting of PDGFRA-altered high-grade glioma with avapritinib

Affiliations

Effective targeting of PDGFRA-altered high-grade glioma with avapritinib

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Miscellaneous