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Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma Claudia C

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Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma Claudia C Published OnlineFirst November 12, 2014; DOI: 10.1158/0008-5472.CAN-13-3629 Cancer Therapeutics, Targets, and Chemical Biology Research Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma Claudia C. Faria1,2, Brian J. Golbourn1, Adrian M. Dubuc1,3, Marc Remke1,3, Roberto J. Diaz1, Sameer Agnihotri1, Amanda Luck1, Nesrin Sabha1, Samantha Olsen1, Xiaochong Wu1,3, Livia Garzia1,3, Vijay Ramaswamy1,3, Stephen C. Mack1,3, Xin Wang1,3, Michael Leadley4, Denis Reynaud4, Leonardo Ermini4, Martin Post4, Paul A. Northcott5, Stefan M. Pfister5, Sidney E.Croul1, Marcel Kool5, Andrey Korshunov6,Christian A. Smith1, Michael D.Taylor1,3,7, and James T. Rutka1,7,8 Abstract Medulloblastoma is the most common malignant pediatric toma may benefit from MET-targeted therapy. In support of this brain tumor, with metastases present at diagnosis conferring a hypothesis, we found that the approved MET inhibitor fore- poor prognosis. Mechanisms of dissemination are poorly tinib could suppress MET activation, decrease tumor cell pro- understood and metastatic lesions are genetically divergent liferation, and induce apoptosis in SHH medulloblastomas from the matched primary tumor. Effective and less toxic in vitro and in vivo. Foretinib penetrated the blood–brain barrier therapies that target both compartments have yet to be iden- and was effective in both the primary and metastatic tumor tified. Here, we report that the analysis of several large non- compartments. In established mouse xenograft or transgenic overlapping cohorts of patients with medulloblastoma reveals models of metastatic SHH medulloblastoma, foretinib admin- MET kinase as a marker of sonic hedgehog (SHH)–driven istration reduced the growth of the primary tumor, decreased medulloblastoma. Immunohistochemical analysis of phos- the incidence of metastases, and increased host survival. Taken phorylated, active MET kinase in an independent patient cohort together, our results provide a strong rationale to clinically confirmed its correlation with increased tumor relapse and evaluate foretinib as an effective therapy for patients with SHH- poor survival, suggesting that patients with SHH medulloblas- driven medulloblastoma. Cancer Res; 75(1); 134–46. Ó2014 AACR. Introduction majority of survivors suffer from severe neurocognitive deficits induced by the deleterious effects of treatment on the developing Medulloblastoma, the most common malignant brain tumor nervous system (1). The discovery of novel and less toxic therapies in childhood, has a high tendency to disseminate through the has been hampered by the poor understanding of the mechanisms cerebrospinal fluid to the brain and the spinal cord leptome- of dissemination, and by the failure to account for the genetic ninges. Dissemination is a known factor of poor survival and divergence between metastatic lesions and their matched primary occurs in one third of the children at the time of diagnosis and in tumor. Recent studies have shed light into the candidate genes two thirds by the time of relapse. Affected children are treated with that drive leptomeningeal dissemination in medulloblastoma craniospinal radiation and high-dose chemotherapy but the (2, 3), but therapies that target both the primary and the meta- static compartment have not been identified. 1Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for The hepatocyte growth factor (HGF)/cMET pathway is essential Sick Children, Toronto, Canada. 2Department of Neurosurgery, Hospi- for cell proliferation and migration during embryogenesis (4) tal de Santa Maria, Centro Hospitalar Lisboa Norte, EPE, Lisbon, and, in the central nervous system, it plays a critical role in Portugal. 3Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada. 4Program in Physiology & Exper- cerebellar development (5). Aberrant cMET signaling is known imental Medicine, Hospital for Sick Children, Toronto, Canada. 5Divi- to be involved in tumor growth and metastatic behavior of several sion of Pediatric Neurooncology and Division of Molecular Genetics, human cancers (6, 7). The transmembrane receptor cMET is German Cancer Research Centre (DKFZ), University of Heidelberg, activated through phosphorylation of tyrosine residues upon Heidelberg, Germany. 6Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), Department of Neuropa- binding of its ligand HGF, which triggers multiple downstream thology, University of Heidelberg, Heidelberg, Germany. 7Division of effector cascades including MAPK and PI3K/AKT that function in 8 Neurosurgery, Hospital for Sick Children, Toronto, Canada. Depart- various cellular processes including cell proliferation, cell surviv- ment of Surgery, University of Toronto, Toronto, Canada. al, migration, and invasion (8). In medulloblastoma, cMET Note: Supplementary data for this article are available at Cancer Research activation is associated with tumor growth and anaplastic histol- Online (http://cancerres.aacrjournals.org/). ogy (9). cMET signaling is deregulated in medulloblastoma Corresponding Author: James T. Rutka, The Hospital for Sick Children, 555 through multiple, independent molecular mechanisms including  University Avenue, Suite 1503, Toronto, ON M5G 1 8, Canada. Phone: 416-813- epigenetic silencing of an upstream inhibitor, the serine protease 6425; Fax: 416-813-4975; E-mail: [email protected] inhibitor Kunitz-type 2 (SPINT2; refs. 10, 11). Previous studies have doi: 10.1158/0008-5472.CAN-13-3629 shown that cMET inhibition can effectively decrease medullo- Ó2014 American Association for Cancer Research. blastoma cell migration and invasion (12). 134 Cancer Res; 75(1) January 1, 2015 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst November 12, 2014; DOI: 10.1158/0008-5472.CAN-13-3629 Foretinib Treatment in Metastatic SHH Medulloblastoma Foretinib is an orally available multikinase inhibitor that 1% v/v DMSO for 2 hours, and stimulated with human recom- targets cMET with high affinity (IC50 ¼ 0.4 nmol/L; ref. 13). binant HGF (20 ng/mL; Sigma-Aldrich) for 20 minutes or human Foretinib has demonstrated antitumor activity in preclinical PDGF-BB (20 ng/mL; Cell Signaling) for 10 minutes. models of different tumor types (14–16) and clinical trials are currently ongoing to determine its efficacy in various solid, non– Migration and invasion assays central nervous system tumors (17, 18). To date, the ability of The protocols for migration and invasion assays were as foretinib to penetrate the brain is unknown. described previously (34). Foretinib also targets other tyrosine kinases with lower affinity, For the radial migration assays, medulloblastoma cells were including the platelet-derived growth factor receptor beta seeded and allowed to migrate for 24 hours in starved media (PDGFRb) with an IC50 of 9.6 nmol/L. Interestingly, PDGFRb is (0.1% FBS) containing HGF (50 ng/mL) or PDGF-BB (50 ng/mL), known to be overexpressed in metastatic medulloblastoma (19, in the presence or absence of foretinib. The radius of the migrating 20), and targeting the receptor reduces proliferation and migra- cells was measured and compared with the initial radius using a tion of medulloblastoma cell lines (21). Activation of PDGFRb Leica Fluorescent Stereoscope (2.5 magnification). occurs through a similar mechanism to cMET receptor activation, The invasion assays were performed using Matrigel Invasion in which ligand binding (PDGF-BB) induces receptor autopho- Chambers (8 mm pore size; BD Biosciences). Daoy and ONS76 sphorylation and activates downstream signaling via MAPK and cells were incubated for 16 hours with starved media containing AKT (22). dilutions of foretinib. The number of cells per 6 random fields was Therefore, we sought to establish the subgroup-specific role of determined (Â10 magnification) using Volocity software (Perkin cMET and PDGFRb in medulloblastoma, and to test the efficacy Elmer). of foretinib to cross the blood–brain barrier and to target those pathways, both in the primary and in the metastatic Immunoblotting compartments. The following antibodies from Cell Signaling were used: cMET (1:1,000), phospho-cMET (1:1,000), PDGFRb (1:500), phospho- PDGFRb (1:500), AKT (1:1,000), phospho-AKT (1:2,000), p44/ Materials and Methods 42 MAPK (1:1,000), phospho-p44/42 MAPK (1:2,000), PARP Tumor material and patient characteristics (1:1,000), b-actin (1:10,000), anti-rabbit IgG conjugated to All tissues and clinicopathologic information were serially horseradish peroxidase (1:5,000), and anti-mouse IgG conjugat- collected in accordance with Institutional Review Boards from ed to horseradish peroxidase (1:5,000). Western blot analysis and contributing institutions. Nucleic acid extractions were carried out quantification were performed using the Fluorchem Q Imaging as previously described (23). System (ProteinSimple). Cell proliferation assays Expression profiling and molecular subgrouping Medulloblastoma cells were treated with different concentra- Expression of candidate genes was assessed using the R2 soft- tions of foretinib or DMSO, and cell viability was determined for ware in independent gene expression cohorts (24–32). Expression the indicated time points by MTS (3-(4,5-dimethylthiazol-2-yl)- of reported intermediates of MET signaling was visualized using 5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) heatmaps (7). Associations between gene expression and sub- absorbance at 490
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