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© 2025 The Authors. 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.
Author(s): Mayr L, Neyazi S, Schwark K, Trissal M, Beck A, Labelle J, Eder SK, Weiler-Wichtl L, Marques JG, de Biagi-Junior CAO, Lo Cascio C, Chapman O, Sridhar S, Kenkre R, Dutta A, Wang S, Wang J, Hack O, Nascimento A, Nguyen CM, Castellani S, Rozowsky JS, Groves A, Panditharatna E, Cruzeiro GAV, Haase RD, Tabatabai K, Madlener S, Wadden J, Adam T, Kong S, Miclea M, Patel T, Bruckner K, Senfter D, Lammerer A, Supko J, Guntner AS, Palova H, Neradil J, Stepien N, Lotsch-Gojo D, Berger W, Leiss U, Rosenmayr V, Dorfer C, Dieckmann K, Peyrl A, Azizi AA, Baumgartner A, Slaby O, Pokorna P, Clark LM, Cameron A, Nguyen Q-D, Wakimoto H, Dubois F, Greenwald NF, Bandopadhayay P, Beroukhim R, Ligon K, Kramm C, Bronsema A, Bailey S, Stucklin AG, Mueller S, Skrypek M, Martinez N, Bowers DC, Jones DTW, Jones C, Jager N, Sterba J, Mullauer L, Haberler C, Kumar-Sinha C, Chinnaiyan A, Mody R, Chavez L, Furtner J, Koschmann C, Gojo J, Filbin MG
Publication type: Article
Publication status: Published
Journal: Cancer Cell
Year: 2025
Pages: Epub ahead of print
Online publication date: 13/03/2025
Acceptance date: 12/02/2025
Date deposited: 31/03/2025
ISSN (print): 1535-6108
ISSN (electronic): 1878-3686
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ccell.2025.02.018
DOI: 10.1016/j.ccell.2025.02.018
Data Access Statement: Published pHGG genomic datasets analyzed for PDGFRA alterations are included in previous work and at the Children’s Brain Tumor Network (www.cbtn.org). Unpublished data of 69 samples sequenced through the Michigan Oncology Sequencing Center (MI-ONCOSEQ) are available in Table S2. For the second genomic analysis, focusing specifically on chromosomal and extrachromosomal PDGFRA amplifications, WGS data from the CBTN and St. Jude datasets are available from the following sources upon approval from an institutional data access committee [Please see the article for the full list of sources and the full data availability statement].
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