Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy

Background 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 a...

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Published in:	Molecular cancer Vol. 23; no. 1; pp. 123 - 19
Main Authors:	Zuckermann, Marc, He, Chen, Andrews, Jared, Bagchi, Aditi, Sloan-Henry, Roketa, Bianski, Brandon, Xie, Jia, Wang, Yingzhe, Twarog, Nathaniel, Onar-Thomas, Arzu, Ernst, Kati J., Yang, Lei, Li, Yong, Zhu, Xiaoyan, Ocasio, Jennifer K., Budd, Kaitlin M., Dalton, James, Li, Xiaoyu, Chepyala, Divyabharathi, Zhang, Junyuan, Xu, Ke, Hover, Laura, Roach, Jordan T., Chan, Kenneth Chun-Ho, Hofmann, Nina, McKinnon, Peter J., Pfister, Stefan M., Shelat, Anang A., Rankovic, Zoran, Freeman, Burgess B., Chiang, Jason, Jones, David T. W., Tinkle, Christopher L., Baker, Suzanne J.
Format:	Journal Article
Language:	English
Published:	London BioMed Central 07.06.2024 BioMed Central Ltd BMC
Subjects:	Anilides - pharmacology Animals Benzamides - pharmacology Benzamides - therapeutic use Biomedical and Life Sciences Biomedicine Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - pathology Brain Neoplasms - radiotherapy Brain tumors Cancer Research Capmatinib Cell Line, Tumor Child Combination therapy Crizotinib - pharmacology Crizotinib - therapeutic use Disease Models, Animal Female Glioma - drug therapy Glioma - genetics Glioma - pathology Glioma - therapy Gliomas Humans Imidazoles MET inhibition Mice Neoplasm Grading Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Oncology Pediatric-type diffuse high-grade glioma Pediatrics Preclinical trials Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins c-met - antagonists & inhibitors Proto-Oncogene Proteins c-met - genetics Proto-Oncogene Proteins c-met - metabolism Pyridines - pharmacology Pyridines - therapeutic use Radiation Radiosensitization Radiotherapy Triazines Tyrosine Xenograft Model Antitumor Assays Pediatric-type diffuse high-grade glioma MET inhibition Radiosensitization Combination therapy Capmatinib Preclinical trials
ISSN:	1476-4598, 1476-4598
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Summary:	Background 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. Methods 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. Results 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. Conclusions 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1476-4598 1476-4598
DOI:	10.1186/s12943-024-02027-6