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000290898 1001_ $$0P:(DE-He78)2a8fbc2efe7e5e468472d57f724fe39b$$aZuckermann, Marc$$b0$$eFirst author$$udkfz
000290898 245__ $$aCapmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.
000290898 260__ $$aLondon$$bBiomed Central$$c2024
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000290898 520__ $$aPediatric-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.
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000290898 650_7 $$2Other$$aCapmatinib
000290898 650_7 $$2Other$$aCombination therapy
000290898 650_7 $$2Other$$aMET inhibition
000290898 650_7 $$2Other$$aPediatric-type diffuse high-grade glioma
000290898 650_7 $$2Other$$aPreclinical trials
000290898 650_7 $$2Other$$aRadiosensitization
000290898 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aProto-Oncogene Proteins c-met
000290898 650_7 $$0TY34L4F9OZ$$2NLM Chemicals$$acapmatinib
000290898 650_7 $$2NLM Chemicals$$aBenzamides
000290898 650_7 $$2NLM Chemicals$$aOncogene Proteins, Fusion
000290898 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aMET protein, human
000290898 650_7 $$2NLM Chemicals$$aProtein Kinase Inhibitors
000290898 650_7 $$2NLM Chemicals$$aPyridines
000290898 650_7 $$053AH36668S$$2NLM Chemicals$$aCrizotinib
000290898 650_7 $$2NLM Chemicals$$aAnilides
000290898 650_7 $$01C39JW444G$$2NLM Chemicals$$acabozantinib
000290898 650_7 $$2NLM Chemicals$$aImidazoles
000290898 650_7 $$2NLM Chemicals$$aTriazines
000290898 650_2 $$2MeSH$$aAnimals
000290898 650_2 $$2MeSH$$aHumans
000290898 650_2 $$2MeSH$$aGlioma: pathology
000290898 650_2 $$2MeSH$$aGlioma: drug therapy
000290898 650_2 $$2MeSH$$aGlioma: genetics
000290898 650_2 $$2MeSH$$aGlioma: therapy
000290898 650_2 $$2MeSH$$aProto-Oncogene Proteins c-met: antagonists & inhibitors
000290898 650_2 $$2MeSH$$aProto-Oncogene Proteins c-met: genetics
000290898 650_2 $$2MeSH$$aProto-Oncogene Proteins c-met: metabolism
000290898 650_2 $$2MeSH$$aMice
000290898 650_2 $$2MeSH$$aXenograft Model Antitumor Assays
000290898 650_2 $$2MeSH$$aBrain Neoplasms: pathology
000290898 650_2 $$2MeSH$$aBrain Neoplasms: drug therapy
000290898 650_2 $$2MeSH$$aBrain Neoplasms: genetics
000290898 650_2 $$2MeSH$$aBrain Neoplasms: radiotherapy
000290898 650_2 $$2MeSH$$aBenzamides: pharmacology
000290898 650_2 $$2MeSH$$aBenzamides: therapeutic use
000290898 650_2 $$2MeSH$$aCell Line, Tumor
000290898 650_2 $$2MeSH$$aOncogene Proteins, Fusion: genetics
000290898 650_2 $$2MeSH$$aOncogene Proteins, Fusion: metabolism
000290898 650_2 $$2MeSH$$aFemale
000290898 650_2 $$2MeSH$$aProtein Kinase Inhibitors: pharmacology
000290898 650_2 $$2MeSH$$aProtein Kinase Inhibitors: therapeutic use
000290898 650_2 $$2MeSH$$aPyridines: pharmacology
000290898 650_2 $$2MeSH$$aPyridines: therapeutic use
000290898 650_2 $$2MeSH$$aCrizotinib: pharmacology
000290898 650_2 $$2MeSH$$aCrizotinib: therapeutic use
000290898 650_2 $$2MeSH$$aDisease Models, Animal
000290898 650_2 $$2MeSH$$aChild
000290898 650_2 $$2MeSH$$aNeoplasm Grading
000290898 650_2 $$2MeSH$$aAnilides: pharmacology
000290898 650_2 $$2MeSH$$aImidazoles
000290898 650_2 $$2MeSH$$aTriazines
000290898 7001_ $$aHe, Chen$$b1
000290898 7001_ $$aAndrews, Jared$$b2
000290898 7001_ $$aBagchi, Aditi$$b3
000290898 7001_ $$aSloan-Henry, Roketa$$b4
000290898 7001_ $$aBianski, Brandon$$b5
000290898 7001_ $$aXie, Jia$$b6
000290898 7001_ $$aWang, Yingzhe$$b7
000290898 7001_ $$aTwarog, Nathaniel$$b8
000290898 7001_ $$aOnar-Thomas, Arzu$$b9
000290898 7001_ $$0P:(DE-He78)bac03ea8237bbc7b1290321d845ddef7$$aErnst, Kati$$b10$$udkfz
000290898 7001_ $$aYang, Lei$$b11
000290898 7001_ $$aLi, Yong$$b12
000290898 7001_ $$aZhu, Xiaoyan$$b13
000290898 7001_ $$aOcasio, Jennifer K$$b14
000290898 7001_ $$aBudd, Kaitlin M$$b15
000290898 7001_ $$aDalton, James$$b16
000290898 7001_ $$aLi, Xiaoyu$$b17
000290898 7001_ $$aChepyala, Divyabharathi$$b18
000290898 7001_ $$aZhang, Junyuan$$b19
000290898 7001_ $$aXu, Ke$$b20
000290898 7001_ $$aHover, Laura$$b21
000290898 7001_ $$aRoach, Jordan T$$b22
000290898 7001_ $$0P:(DE-HGF)0$$aChan, Kenneth Chun-Ho$$b23
000290898 7001_ $$0P:(DE-He78)9947809cec435f1935fa834b6fbd97d2$$aHofmann, Nina$$b24$$udkfz
000290898 7001_ $$aMcKinnon, Peter J$$b25
000290898 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b26$$udkfz
000290898 7001_ $$aShelat, Anang A$$b27
000290898 7001_ $$aRankovic, Zoran$$b28
000290898 7001_ $$aFreeman, Burgess B$$b29
000290898 7001_ $$aChiang, Jason$$b30
000290898 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b31$$eLast author$$udkfz
000290898 7001_ $$aTinkle, Christopher L$$b32
000290898 7001_ $$aBaker, Suzanne J$$b33
000290898 773__ $$0PERI:(DE-600)2091373-4$$a10.1186/s12943-024-02027-6$$gVol. 23, no. 1, p. 123$$n1$$p123$$tMolecular cancer$$v23$$x1476-4598$$y2024
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