Journal Article

DKFZ-2024-01237

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

Zuckermann, M. (First author)DKFZ* ; He, C. ; Andrews, J. ; Bagchi, A. ; Sloan-Henry, R. ; Bianski, B. ; Xie, J. ; Wang, Y. ; Twarog, N. ; Onar-Thomas, A. ; Ernst, K.DKFZ* ; Yang, L. ; Li, Y. ; Zhu, X. ; Ocasio, J. K. ; Budd, K. M. ; Dalton, J. ; Li, X. ; Chepyala, D. ; Zhang, J. ; Xu, K. ; Hover, L. ; Roach, J. T. ; Chan, K. C.DKFZ* ; Hofmann, N.DKFZ* ; McKinnon, P. J. ; Pfister, S.DKFZ* ; Shelat, A. A. ; Rankovic, Z. ; Freeman, B. B. ; Chiang, J. ; Jones, D. (Last author)DKFZ* ; Tinkle, C. L. ; Baker, S. J.

2024
Biomed Central London

This record in other databases:  

Please use a persistent id in citations: doi:10.1186/s12943-024-02027-6

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.

Keyword(s): Animals (MeSH) ; Humans (MeSH) ; Glioma: pathology (MeSH) ; Glioma: drug therapy (MeSH) ; Glioma: genetics (MeSH) ; Glioma: therapy (MeSH) ; Proto-Oncogene Proteins c-met: antagonists & inhibitors (MeSH) ; Proto-Oncogene Proteins c-met: genetics (MeSH) ; Proto-Oncogene Proteins c-met: metabolism (MeSH) ; Mice (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Brain Neoplasms: drug therapy (MeSH) ; Brain Neoplasms: genetics (MeSH) ; Brain Neoplasms: radiotherapy (MeSH) ; Benzamides: pharmacology (MeSH) ; Benzamides: therapeutic use (MeSH) ; Cell Line, Tumor (MeSH) ; Oncogene Proteins, Fusion: genetics (MeSH) ; Oncogene Proteins, Fusion: metabolism (MeSH) ; Female (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; Protein Kinase Inhibitors: therapeutic use (MeSH) ; Pyridines: pharmacology (MeSH) ; Pyridines: therapeutic use (MeSH) ; Crizotinib: pharmacology (MeSH) ; Crizotinib: therapeutic use (MeSH) ; Disease Models, Animal (MeSH) ; Child (MeSH) ; Neoplasm Grading (MeSH) ; Anilides: pharmacology (MeSH) ; Imidazoles (MeSH) ; Triazines (MeSH) ; Capmatinib ; Combination therapy ; MET inhibition ; Pediatric-type diffuse high-grade glioma ; Preclinical trials ; Radiosensitization ; Proto-Oncogene Proteins c-met ; capmatinib ; Benzamides ; Oncogene Proteins, Fusion ; MET protein, human ; Protein Kinase Inhibitors ; Pyridines ; Crizotinib ; Anilides ; cabozantinib ; Imidazoles ; Triazines

Note: #EA:B062#EA:B360#LA:B360#

---

Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. Pädiatrische Gliomforschung (B360)
3. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

---

Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 30 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---