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@ARTICLE{Faria:126496,
author = {C. C. Faria and B. J. Golbourn and A. M. Dubuc and M. Remke
and R. J. Diaz and S. Agnihotri and A. Luck and N. Sabha and
S. Olsen and X. Wu and L. Garzia and V. Ramaswamy$^*$ and S.
C. Mack and X. Wang and M. Leadley and D. Reynaud and L.
Ermini and M. Post and P. A. Northcott$^*$ and S.
Pfister$^*$ and S. E. Croul and M. Kool$^*$ and A.
Korshunov$^*$ and C. A. Smith and M. D. Taylor and J. T.
Rutka},
title = {{F}oretinib is effective therapy for metastatic sonic
hedgehog medulloblastoma.},
journal = {Cancer research},
volume = {75},
number = {1},
issn = {1538-7445},
address = {Philadelphia, Pa.},
publisher = {AACR},
reportid = {DKFZ-2017-02525},
pages = {134 - 146},
year = {2015},
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 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.},
keywords = {Anilides (NLM Chemicals) / GSK 1363089 (NLM Chemicals) /
Hedgehog Proteins (NLM Chemicals) / Quinolines (NLM
Chemicals) / SHH protein, human (NLM Chemicals) /
Proto-Oncogene Proteins c-met (NLM Chemicals) / Receptor,
Platelet-Derived Growth Factor beta (NLM Chemicals)},
cin = {B062 / G380},
ddc = {610},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)G380-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25391241},
doi = {10.1158/0008-5472.CAN-13-3629},
url = {https://inrepo02.dkfz.de/record/126496},
}