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000126496 0247_ $$2doi$$a10.1158/0008-5472.CAN-13-3629
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000126496 0247_ $$2ISSN$$a0099-7374
000126496 0247_ $$2ISSN$$a1538-7445
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000126496 1001_ $$aFaria, Claudia C$$b0
000126496 245__ $$aForetinib is effective therapy for metastatic sonic hedgehog medulloblastoma.
000126496 260__ $$aPhiladelphia, Pa.$$bAACR$$c2015
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000126496 520__ $$aMedulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)-driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma.
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000126496 650_7 $$2NLM Chemicals$$aAnilides
000126496 650_7 $$2NLM Chemicals$$aGSK 1363089
000126496 650_7 $$2NLM Chemicals$$aHedgehog Proteins
000126496 650_7 $$2NLM Chemicals$$aQuinolines
000126496 650_7 $$2NLM Chemicals$$aSHH protein, human
000126496 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aProto-Oncogene Proteins c-met
000126496 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aReceptor, Platelet-Derived Growth Factor beta
000126496 7001_ $$aGolbourn, Brian J$$b1
000126496 7001_ $$aDubuc, Adrian M$$b2
000126496 7001_ $$aRemke, Marc$$b3
000126496 7001_ $$aDiaz, Roberto J$$b4
000126496 7001_ $$aAgnihotri, Sameer$$b5
000126496 7001_ $$aLuck, Amanda$$b6
000126496 7001_ $$aSabha, Nesrin$$b7
000126496 7001_ $$aOlsen, Samantha$$b8
000126496 7001_ $$aWu, Xiaochong$$b9
000126496 7001_ $$aGarzia, Livia$$b10
000126496 7001_ $$0P:(DE-HGF)0$$aRamaswamy, Vijay$$b11
000126496 7001_ $$aMack, Stephen C$$b12
000126496 7001_ $$aWang, Xin$$b13
000126496 7001_ $$aLeadley, Michael$$b14
000126496 7001_ $$aReynaud, Denis$$b15
000126496 7001_ $$aErmini, Leonardo$$b16
000126496 7001_ $$aPost, Martin$$b17
000126496 7001_ $$0P:(DE-HGF)0$$aNorthcott, Paul A$$b18
000126496 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b19$$udkfz
000126496 7001_ $$aCroul, Sidney E$$b20
000126496 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b21$$udkfz
000126496 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b22$$udkfz
000126496 7001_ $$aSmith, Christian A$$b23
000126496 7001_ $$aTaylor, Michael D$$b24
000126496 7001_ $$aRutka, James T$$b25
000126496 773__ $$0PERI:(DE-600)2036785-5$$a10.1158/0008-5472.CAN-13-3629$$gVol. 75, no. 1, p. 134 - 146$$n1$$p134 - 146$$tCancer research$$v75$$x1538-7445$$y2015
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