Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma

Claudia C. Faria, Brian J. Golbourn, Adrian M. Dubuc, Marc Remke, Roberto J. Diaz, Sameer Agnihotri, Amanda Luck, Nesrin Sabha, Samantha Olsen, Xiaochong Wu, Livia Garzia, Vijay Ramaswamy, Stephen C. Mack, Xin Wang, Michael Leadley, Denis Reynaud, Leonardo Ermini, Martin Post, Paul A. Northcott, Stefan M. PfisterSidney E. Croul, Marcel Kool, Andrey Korshunov, Christian A. Smith, Michael D. Taylor, James T. Rutka

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

Abstract

Medulloblastoma 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 non-overlapping 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 benefi t fromMET-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.

Original languageEnglish
Pages (from-to)134-146
Number of pages13
JournalCancer Research
Volume75
Issue number1
DOIs
Publication statusPublished - 1 Jan 2015
Externally publishedYes

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