title: Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer.
abstract: BACKGROUND
  Unresectable gastric cancer is associated with poor outcomes, with few treatment options available after failure of cytotoxic chemotherapy. Clinical trials of targeted therapies have generally shown no survival benefit in gastric cancer, with the exceptions of the antibodies ramucirumab (anti-VEGFR2) and trastuzumab (anti-HER2/neu). Given the efficacy of the multikinase inhibitor regorafenib in other gastrointestinal tumors, we investigated its potential in gastric cancer.
  
  
  METHODS
  The antitumor activity of oral regorafenib was assessed in eight murine patient-derived gastric cancer xenograft models. Dose-response experiments assessed the efficacy and tolerability of oral regorafenib 5, 10, and 15 mg/kg/day in two models, with 10 mg/kg/day selected for further investigation in all eight models. Tumor weight and volume was monitored during treatment; tumor cell proliferation, angiogenesis, apoptosis, and intracellular signaling were assessed using immunohistochemistry and Western blotting of total tumor lysates at the end of treatment.
  
  
  RESULTS
  Regorafenib showed dose-dependent inhibition of tumor growth and was well tolerated, with no significant decreases in bodyweight or evident toxicity. Regorafenib 10 mg/kg/day significantly inhibited tumor growth in all eight models (72 to 96 %; all p < 0.01), resulting in reduced tumor weight versus vehicle controls. Regorafenib reduced tumor angiogenesis 3- to 11-fold versus controls in all models (all p < 0.05), reduced tumor proliferation 2- to 5-fold in six of the eight models (all p < 0.05), and induced apoptosis in seven models.
  
  
  CONCLUSIONS
  Regorafenib was effective in patient-derived models of gastric cancer of different histological subtypes, with inhibition of tumor growth, angiogenesis, and tumor-cell proliferation observed in almost all models. These findings are consistent with the observed activity of regorafenib in preclinical models of other gastrointestinal tumors, and support further clinical investigation in gastric cancer.
authors.affiliation: Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. cmrhth@nccs.com.sg.
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.affiliation: Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore. richard.ong.w.j@nccs.com.sg.
authors.forename: Richard
authors.initials: R
authors.lastname: Ong
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany. dieter.zopf@bayer.com.
authors.forename: Dieter
authors.initials: D
authors.lastname: Zopf
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib