title: Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis.
abstract: BACKGROUND
  Medulloblastoma is the most common malignant brain tumor in children. Current standard treatments cure 40%-60% of patients, while the majority of survivors suffer long-term neurological sequelae. The identification of 4 molecular groups of medulloblastoma improved the clinical management with the development of targeted therapies; however, the tumor acquires resistance quickly. Mebendazole (MBZ) has a long safety record as antiparasitic in children and has been recently implicated in inhibition of various tyrosine kinases in vitro. Here, we investigated the efficacy of MBZ in various medulloblastoma subtypes and MBZ's impact on vascular endothelial growth factor receptor 2 (VEGFR2) and tumor angiogenesis.
  
  
  METHODS
  The inhibition of MBZ on VEGFR2 kinase was investigated in an autophosphorylation assay and a cell-free kinase assay. Mice bearing orthotopic PTCH1-mutant medulloblastoma allografts, a group 3 medulloblastoma xenograft, and a PTCH1-mutant medulloblastoma with acquired resistance to the smoothened inhibitor vismodegib were treated with MBZ. The survival benefit and the impact on tumor angiogenesis and VEGFR2 kinase function were analyzed.
  
  
  RESULTS
  We determined that MBZ interferes with VEGFR2 kinase by competing with ATP. MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculatures in orthotopic medulloblastoma models and suppressed VEGFR2 kinase in vivo. MBZ significantly extended the survival of medulloblastoma models derived from different molecular backgrounds.
  
  
  CONCLUSIONS
  Our findings support testing of MBZ as a possible low-toxicity therapy for medulloblastomas of various molecular subtypes, including tumors with acquired vismodegib resistance. Its antitumor mechanism may be partially explained by inhibition of tumor angiogenesis.
authors.affiliation: Department of Neurosurgery (R.-Y.B., G.J.R.), Department of Neurology (V.S.); Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (F.B.); Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (C.M.R.).
authors.forename: Ren-Yuan
authors.initials: RY
authors.lastname: Bai
authors.affiliation: Department of Neurosurgery (R.-Y.B., G.J.R.), Department of Neurology (V.S.); Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (F.B.); Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (C.M.R.).
authors.forename: Verena
authors.initials: V
authors.lastname: Staedtke
authors.affiliation: Department of Neurosurgery (R.-Y.B., G.J.R.), Department of Neurology (V.S.); Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (F.B.); Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (C.M.R.).
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Department of Neurosurgery (R.-Y.B., G.J.R.), Department of Neurology (V.S.); Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (F.B.); Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (C.M.R.).
authors.forename: Fred
authors.initials: F
authors.lastname: Bunz
authors.affiliation: Department of Neurosurgery (R.-Y.B., G.J.R.), Department of Neurology (V.S.); Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (F.B.); Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (C.M.R.).
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D006801:Humans; D008463:Mebendazole / Q000627:therapeutic use*; D008527:Medulloblastoma / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008463:Mebendazole; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: VEGF; VEGFR2; angiogenesis; mebendazole; medulloblastoma