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@ARTICLE{Zuckermann:290898,
      author       = {M. Zuckermann$^*$ and C. He and J. Andrews and A. Bagchi
                      and R. Sloan-Henry and B. Bianski and J. Xie and Y. Wang and
                      N. Twarog and A. Onar-Thomas and K. Ernst$^*$ and L. Yang
                      and Y. Li and X. Zhu and J. K. Ocasio and K. M. Budd and J.
                      Dalton and X. Li and D. Chepyala and J. Zhang and K. Xu and
                      L. Hover and J. T. Roach and K. C. Chan$^*$ and N.
                      Hofmann$^*$ and P. J. McKinnon and S. Pfister$^*$ and A. A.
                      Shelat and Z. Rankovic and B. B. Freeman and J. Chiang and
                      D. Jones$^*$ and C. L. Tinkle and S. J. Baker},
      title        = {{C}apmatinib is an effective treatment for {MET}-fusion
                      driven pediatric high-grade glioma and synergizes with
                      radiotherapy.},
      journal      = {Molecular cancer},
      volume       = {23},
      number       = {1},
      issn         = {1476-4598},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2024-01237},
      pages        = {123},
      year         = {2024},
      note         = {#EA:B062#EA:B360#LA:B360#},
      abstract     = {Pediatric-type diffuse high-grade glioma (pHGG) is the most
                      frequent malignant brain tumor in children and can be
                      subclassified into multiple entities. Fusion genes
                      activating the MET receptor tyrosine kinase often occur in
                      infant-type hemispheric glioma (IHG) but also in other pHGG
                      and are associated with devastating morbidity and
                      mortality.To identify new treatment options, we established
                      and characterized two novel orthotopic mouse models
                      harboring distinct MET fusions. These included an
                      immunocompetent, murine allograft model and patient-derived
                      orthotopic xenografts (PDOX) from a MET-fusion IHG patient
                      who failed conventional therapy and targeted therapy with
                      cabozantinib. With these models, we analyzed the efficacy
                      and pharmacokinetic properties of three MET inhibitors,
                      capmatinib, crizotinib and cabozantinib, alone or combined
                      with radiotherapy.Capmatinib showed superior brain
                      pharmacokinetic properties and greater in vitro and in vivo
                      efficacy than cabozantinib or crizotinib in both models. The
                      PDOX models recapitulated the poor efficacy of cabozantinib
                      experienced by the patient. In contrast, capmatinib extended
                      survival and induced long-term progression-free survival
                      when combined with radiotherapy in two complementary mouse
                      models. Capmatinib treatment increased radiation-induced DNA
                      double-strand breaks and delayed their repair.We
                      comprehensively investigated the combination of MET
                      inhibition and radiotherapy as a novel treatment option for
                      MET-driven pHGG. Our seminal preclinical data package
                      includes pharmacokinetic characterization, recapitulation of
                      clinical outcomes, coinciding results from multiple
                      complementing in vivo studies, and insights into molecular
                      mechanism underlying increased efficacy. Taken together, we
                      demonstrate the groundbreaking efficacy of capmatinib and
                      radiation as a highly promising concept for future clinical
                      trials.},
      keywords     = {Animals / Humans / Glioma: pathology / Glioma: drug therapy
                      / Glioma: genetics / Glioma: therapy / Proto-Oncogene
                      Proteins c-met: antagonists $\&$ inhibitors / Proto-Oncogene
                      Proteins c-met: genetics / Proto-Oncogene Proteins c-met:
                      metabolism / Mice / Xenograft Model Antitumor Assays / Brain
                      Neoplasms: pathology / Brain Neoplasms: drug therapy / Brain
                      Neoplasms: genetics / Brain Neoplasms: radiotherapy /
                      Benzamides: pharmacology / Benzamides: therapeutic use /
                      Cell Line, Tumor / Oncogene Proteins, Fusion: genetics /
                      Oncogene Proteins, Fusion: metabolism / Female / Protein
                      Kinase Inhibitors: pharmacology / Protein Kinase Inhibitors:
                      therapeutic use / Pyridines: pharmacology / Pyridines:
                      therapeutic use / Crizotinib: pharmacology / Crizotinib:
                      therapeutic use / Disease Models, Animal / Child / Neoplasm
                      Grading / Anilides: pharmacology / Imidazoles / Triazines /
                      Capmatinib (Other) / Combination therapy (Other) / MET
                      inhibition (Other) / Pediatric-type diffuse high-grade
                      glioma (Other) / Preclinical trials (Other) /
                      Radiosensitization (Other) / Proto-Oncogene Proteins c-met
                      (NLM Chemicals) / capmatinib (NLM Chemicals) / Benzamides
                      (NLM Chemicals) / Oncogene Proteins, Fusion (NLM Chemicals)
                      / MET protein, human (NLM Chemicals) / Protein Kinase
                      Inhibitors (NLM Chemicals) / Pyridines (NLM Chemicals) /
                      Crizotinib (NLM Chemicals) / Anilides (NLM Chemicals) /
                      cabozantinib (NLM Chemicals) / Imidazoles (NLM Chemicals) /
                      Triazines (NLM Chemicals)},
      cin          = {B062 / B360 / HD01},
      ddc          = {570},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)B360-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38849845},
      pmc          = {pmc:PMC11157767},
      doi          = {10.1186/s12943-024-02027-6},
      url          = {https://inrepo02.dkfz.de/record/290898},
}