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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-03-13 DOI:10.1016/j.ccell.2025.02.018

Lisa Mayr, Sina Neyazi, Kallen Schwark, Maria Trissal, Alexander Beck, Jenna Labelle, Sebastian K. Eder, Liesa Weiler-Wichtl, Joana G. Marques, Carlos A.O. de Biagi-Junior, Costanza Lo Cascio, Owen Chapman, Sunita Sridhar, Rishaan Kenkre, Aditi Dutta, Shanqing Wang, Jessica Wang, Olivia Hack, Andrezza Nascimento, Cuong M. Nguyen, Mariella G. Filbin

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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.

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阿伐替尼有效靶向pdgfr改变的高级别胶质瘤

PDGFRA对肿瘤发生至关重要，在高级别胶质瘤（HGG）中经常发生基因组改变。在儿童HGG的综合数据集中（n = 261），我们在15%的病例中检测到PDGFRA突变和/或扩增，这表明PDGFRA是一种治疗靶点。我们发现PDGFRA/KIT抑制剂avapritinib表现出(1)PDGFRA抑制的选择性，(2)不同的亚细胞效应模式，(3)在患者衍生的HGG模型中体外和体内活性，(4)在小鼠和人体内有效穿透血脑屏障。此外，我们报告了使用阿伐替尼治疗主要复发/难治性PDGFRA改变的HGG的儿科和青年成人患者的初步临床实际经验（n = 8）。我们的早期数据表明，阿伐替尼耐受性良好，3/7的病例放射学反应，表明阿伐替尼在治疗PDGFRA特异性改变的HGG中具有潜在作用。总之，这些转化结果强调了阿伐替尼抑制PDGFRA对HGG的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.