小儿肿瘤科Daniel C. Bowers小组近日取得一项新成果。经过不懈努力，他们揭示了阿伐替尼有效靶向PDGFRA改变的高级别胶质瘤。该项研究成果发表在2025年3月13日出版的《癌细胞》上。

在儿童HGG的综合数据集中（n=261），课题组人员在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。该研究组发现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，该课题组人员报告了阿伐替尼在主要复发/难治性 PDGFRA改变HGG的儿童和青年成人患者中的初步临床现实经验（n = 8）。他们的早期数据表明，阿伐替尼耐受性良好，在3/7的病例中有放射学反应，这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。

据了解，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。

附：英文原文

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

Author: 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, Sophia Castellani, Jacob S. Rozowsky, Andrew Groves, Eshini Panditharatna, Gustavo Alencastro Veiga Cruzeiro, Rebecca D. Haase, Kuscha Tabatabai, Sibylle Madlener, Jack Wadden, Tiffany Adam, Seongbae Kong, Madeline Miclea, Tirth Patel, Katharina Bruckner, Daniel Senfter, Anna Lmmerer, Jeffrey Supko, Armin S. Guntner, Hana Palova, Jakub Neradil, Natalia Stepien, Daniela Ltsch-Gojo, Walter Berger, Ulrike Leiss, Verena Rosenmayr, Christian Dorfer, Karin Dieckmann, Andreas Peyrl, Amedeo A. Azizi, Alicia Baumgartner, Ondrej Slaby, Petra Pokorna, Louise M. Clark, Amy Cameron, Quang-De Nguyen, Hiroaki Wakimoto, Frank Dubois, Noah F. Greenwald, Pratiti Bandopadhayay, Rameen Beroukhim, Keith Ligon, Christof Kramm, Annika Bronsema, Simon Bailey, Ana Guerreiro Stucklin, Sabine Mueller, Mary Skrypek, Nina Martinez, Daniel C. Bowers

Issue&Volume: 2025-03-13

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.

DOI: 10.1016/j.ccell.2025.02.018

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00070-4