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Effective targeting of PDGFRA-altered high-grade glioma with avapritinib
L. Mayr, S. Neyazi, K. Schwark, M. Trissal, A. Beck, J. Labelle, SK. Eder, L. Weiler-Wichtl, JG. Marques, CAO. de Biagi-Junior, C. Lo Cascio, O. Chapman, S. Sridhar, R. Kenkre, A. Dutta, S. Wang, J. Wang, O. Hack, A. Nascimento, CM. Nguyen, S....
Language English Country United States
Document type Journal Article
Persistent link
https://www.medvik.cz/link/bmc25016113
Grant support
U54 CA274516
NCI NIH HHS - United States
R01 NS124607
NINDS NIH HHS - United States
R01 NS119231
NINDS NIH HHS - United States
P50 CA165962
NCI NIH HHS - United States
DP2 NS127705
NINDS NIH HHS - United States
- MeSH
- Child MeSH
- Adult MeSH
- Glioma * drug therapy genetics pathology MeSH
- Blood-Brain Barrier metabolism MeSH
- Protein Kinase Inhibitors * pharmacology therapeutic use MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mutation MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Brain Neoplasms * drug therapy genetics pathology MeSH
- Child, Preschool MeSH
- Antineoplastic Agents * pharmacology therapeutic use MeSH
- Pyrazoles * pharmacology therapeutic use MeSH
- Pyrroles MeSH
- Receptor, Platelet-Derived Growth Factor alpha * genetics antagonists & inhibitors metabolism MeSH
- Neoplasm Grading MeSH
- Triazines MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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.
Broad Institute of MIT and Harvard Cambridge MA 02142 USA
Central European Institute of Technology Masaryk University 60177 Brno Czech Republic
Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic
Department of Experimental Biology Faculty of Science Masaryk University 61137 Brno Czech Republic
Department of Medicine Massachusetts General Hospital Boston MA 02114 USA
Department of Neurology and Neurological Surgery Jefferson University Philadelphia PA 19107 USA
Department of Neurosurgery Massachusetts General Hospital Harvard Medical School Boston MA 02114 USA
Department of Pathology Medical University of Vienna 1090 Vienna Austria
Department of Pathology University of Michigan Medical School Ann Arbor MI 48109 USA
Department of Pediatric Hematology Oncology Children's Minnesota Minneapolis MN 55404 USA
Department of Pediatrics University of Michigan Medical School Ann Arbor MI 48109 USA
Department of Pediatrics University of Texas Southwestern Medical Center Dallas TX 75390 USA
Department of Radiotherapy Medical University of Vienna 1090 Vienna Austria
Division of Molecular Pathology Institute of Cancer Research SM2 5NG London UK
Great North Childrens Hospital and Newcastle University Newcastle upon Tyne UK
Hopp Children's Cancer Center Heidelberg 69120 Heidelberg Germany
Institute for Analytical and General Chemistry Johannes Kepler University 4040 Linz Austria
International Clinical Research Center St Anne's University Hospital Brno Czech Republic
Newcastle Hospitals NHS Foundation Trust NE1 4LP Newcastle UK
Pediatric Glioma Research Group German Cancer Research Center 69120 Heidelberg Germany
Sanford Burnham Prebys Medical Discovery Institute San Diego CA 92037 USA
References provided by Crossref.org
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