TY  - JOUR
AU  - Faria, Claudia C
AU  - Golbourn, Brian J
AU  - Dubuc, Adrian M
AU  - Remke, Marc
AU  - Diaz, Roberto J
AU  - Agnihotri, Sameer
AU  - Luck, Amanda
AU  - Sabha, Nesrin
AU  - Olsen, Samantha
AU  - Wu, Xiaochong
AU  - Garzia, Livia
AU  - Ramaswamy, Vijay
AU  - Mack, Stephen C
AU  - Wang, Xin
AU  - Leadley, Michael
AU  - Reynaud, Denis
AU  - Ermini, Leonardo
AU  - Post, Martin
AU  - Northcott, Paul A
AU  - Pfister, Stefan
AU  - Croul, Sidney E
AU  - Kool, Marcel
AU  - Korshunov, Andrey
AU  - Smith, Christian A
AU  - Taylor, Michael D
AU  - Rutka, James T
TI  - Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma.
JO  - Cancer research
VL  - 75
IS  - 1
SN  - 1538-7445
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2017-02525
SP  - 134 - 146
PY  - 2015
AB  - 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 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.
KW  - Anilides (NLM Chemicals)
KW  - GSK 1363089 (NLM Chemicals)
KW  - Hedgehog Proteins (NLM Chemicals)
KW  - Quinolines (NLM Chemicals)
KW  - SHH protein, human (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-met (NLM Chemicals)
KW  - Receptor, Platelet-Derived Growth Factor beta (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25391241
DO  - DOI:10.1158/0008-5472.CAN-13-3629
UR  - https://inrepo02.dkfz.de/record/126496
ER  -