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