Journal
NATURE MEDICINE
Volume 22, Issue 11, Pages 1314-1320Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4204
Keywords
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Funding
- PedBrain Tumor Project
- German Cancer Aid [109252]
- German Federal Ministry of Education and Research (BMBF) [01KU1201A, 0315416C, 01GS0883, 031A425A, 01ZX1302]
- German Cancer Research Center-Heidelberg Center for Personalized Oncology (DKFZ-HIPO)
- German Cancer Consortium (DKTK, INFORM project)
- Max Planck Society (Munich, Germany)
- European Union (FP7) [262055]
- Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC) [HA-305]
- German Research Foundation (DFG) [LA2983/2-1]
- EDM Foundation
- Lemos Foundation
- New York University Langone Human Specimen Resource Center, Laura and Isaac Perlmutter Cancer Center
- Cancer Center Support Grant from the National Cancer Institute, US National Institutes of Health [P30 CA16087]
- National Center for the Advancement of Translational Science (NCATS), US National Institutes of Health [UL 1 T12000038]
- Making Headway Foundation
- Dr. Mildred Scheel Foundation Scholarship
- NHS
- ICR
- Cancer Research UK [11736, 13982] Funding Source: researchfish
- The Brain Tumour Charity [6/78, 16/193] Funding Source: researchfish
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Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in similar to 10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.
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