Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma.
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.
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal.
Claudia C
CC
Faria
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Brian J
BJ
Golbourn
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
Adrian M
AM
Dubuc
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
Marc
M
Remke
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Roberto J
RJ
Diaz
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Sameer
S
Agnihotri
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Amanda
A
Luck
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Nesrin
N
Sabha
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Samantha
S
Olsen
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
Xiaochong
X
Wu
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
Livia
L
Garzia
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
Vijay
V
Ramaswamy
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
Stephen C
SC
Mack
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
Xin
X
Wang
Program in Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Michael
M
Leadley
Program in Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Denis
D
Reynaud
Program in Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Leonardo
L
Ermini
Program in Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Martin
M
Post
Division of Pediatric Neurooncology and Division of Molecular Genetics, German Cancer Research Centre (DKFZ), University of Heidelberg, Heidelberg, Germany.
Paul A
PA
Northcott
Division of Pediatric Neurooncology and Division of Molecular Genetics, German Cancer Research Centre (DKFZ), University of Heidelberg, Heidelberg, Germany.
Stefan M
SM
Pfister
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Sidney E
SE
Croul
Division of Pediatric Neurooncology and Division of Molecular Genetics, German Cancer Research Centre (DKFZ), University of Heidelberg, Heidelberg, Germany.
Marcel
M
Kool
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.
Andrey
A
Korshunov
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.
Christian A
CA
Smith
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada. Division of Neurosurgery, Hospital for Sick Children, Toronto, Canada.
Michael D
MD
Taylor
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada. Division of Neurosurgery, Hospital for Sick Children, Toronto, Canada. Department of Surgery, University of Toronto, Toronto, Canada. james.rutka@sickkids.ca.
James T
JT
Rutka
D000813:Anilides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000813:Anilides; C544831:GSK 1363089; D053823:Hedgehog Proteins; D011804:Quinolines; C509239:SHH protein, human; D019859:Proto-Oncogene Proteins c-met; D020797:Receptor, Platelet-Derived Growth Factor beta