Effective targeting of PDGFRA-altered high-grade glioma with avapritinib PMID: 40086436

ADC Targets in Oncology

2026-04-10

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

Cancer Cell. 2025 Mar 13:S1535-6108(25)00070-4. doi: 10.1016/j.ccell.2025.02.018.

Lisa Mayr ¹ , Sina Neyazi ² , Kallen Schwark ³ , Maria Trissal ² , Alexander Beck ⁴ , Jenna Labelle ² , Sebastian K Eder ⁵ , Liesa Weiler-Wichtl ⁶ , Joana G Marques ² , Carlos A O de Biagi-Junior ² , Costanza Lo Cascio ² , Owen Chapman ⁷ , Sunita Sridhar ⁷ , Rishaan Kenkre ⁷ , Aditi Dutta ⁷ , Shanqing Wang ⁷ , Jessica Wang ⁷ , Olivia Hack ² , Andrezza Nascimento ² , Cuong M Nguyen ² , Sophia Castellani ² , Jacob S Rozowsky ² , Andrew Groves ² , Eshini Panditharatna ² , Gustavo Alencastro Veiga Cruzeiro ² , Rebecca D Haase ² , Kuscha Tabatabai ² , Sibylle Madlener ⁶ , Jack Wadden ³ , Tiffany Adam ³ , Seongbae Kong ³ , Madeline Miclea ³ , Tirth Patel ³ , Katharina Bruckner ⁸ , Daniel Senfter ⁶ , Anna Lämmerer ⁹ , Jeffrey Supko ¹⁰ , Armin S Guntner ¹¹ , Hana Palova ¹² , Jakub Neradil ¹³ , Natalia Stepien ⁶ , Daniela Lötsch-Gojo ¹⁴ , Walter Berger ¹⁵ , Ulrike Leiss ⁶ , Verena Rosenmayr ⁶ , Christian Dorfer ¹⁴ , Karin Dieckmann ¹⁶ , Andreas Peyrl ⁶ , Amedeo A Azizi ⁶ , Alicia Baumgartner ¹ , Ondrej Slaby ¹⁷ , Petra Pokorna ¹² , Louise M Clark ¹⁸ , Amy Cameron ¹⁸ , Quang-De Nguyen ¹⁸ , Hiroaki Wakimoto ¹⁹ , Frank Dubois ² , Noah F Greenwald ²⁰ , Pratiti Bandopadhayay ² , Rameen Beroukhim ²¹ , Keith Ligon ² , Christof Kramm ²² , Annika Bronsema ²³ , Simon Bailey ²⁴ , Ana Guerreiro Stucklin ²⁵ , Sabine Mueller ²⁶ , Mary Skrypek ²⁷ , Nina Martinez ²⁸ , Daniel C Bowers ²⁹ , David T W Jones ³⁰ , Chris Jones ³¹ , Natalie Jäger ³² , Jaroslav Sterba ³³ , Leonhard Müllauer ³⁴ , Christine Haberler ³⁵ , Chandan Kumar-Sinha ³⁶ , Arul Chinnaiyan ³⁶ , Rajen Mody ³ , Lukas Chavez ⁷ , Julia Furtner ³⁷ , Carl Koschmann ³⁸ , Johannes Gojo ³⁹ , Mariella G Filbin ⁴⁰

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: [email protected].
39. Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: [email protected].
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: [email protected].

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.