title: Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis.
abstract: OBJECTIVE
  Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth.
  
  
  METHODS
  The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum.
  
  
  RESULTS
  In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G(2)-M cell-cycle arrest, and (e) induction of anoikis.
  
  
  CONCLUSIONS
  This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer.
authors.affiliation: Departments of Obstetrics and Gynecology/Section of Gynecologic Oncology-Center for Integrative Science and Pathology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Zillhardt
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Park
authors.forename: Iris L
authors.initials: IL
authors.lastname: Romero
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.forename: Anthony
authors.initials: A
authors.lastname: Montag
authors.forename: Thomas
authors.initials: T
authors.lastname: Krausz
authors.forename: S Diane
authors.initials: SD
authors.lastname: Yamada
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Peter
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
mesh_terms: D000284:Administration, Oral; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D023102:Anoikis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C544831:GSK 1363089; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2