title: Preclinical evaluation of a novel c-Met inhibitor in a gastric cancer xenograft model using small animal PET.
abstract: OBJECTIVE
  Here, we describe the efficacy of the novel small molecule c-Met inhibitor BAY 853474 in reducing tumor growth in the Hs746T gastric cancer xenograft model and tested the suitability of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) versus 3'-deoxy-3'-18F-fluorothymidine ([(18)F]FLT) for response monitoring in a gastric cancer xenograft mouse model using small animal PET.
  
  
  METHODS
  The c-Met inhibitor or vehicle control was administered orally at various doses in tumor-bearing mice. Glucose uptake and proliferation was measured using PET before, 48 and 96 h after the first treatment. The PET data were compared to data from tumor growth curves, autoradiography, Glut-1 and Ki-67 staining of tumor sections, and biochemical analysis of tissue probes, i.e., c-Met and ERK phosphorylation and cyclin D1 levels.
  
  
  RESULTS
  BAY 853474 significantly reduces tumor growth. [(18)F]FDG uptake in Hs746T tumors was significantly reduced in the groups receiving the drug, compared with the control group. The [(18)F]FLT uptake in the tumor tissue was completely absent 96 h after treatment. Autoradiographic, immunohistochemical, and biochemical analyses confirmed the PET findings. Treatment with the c-Met inhibitor did not affect body weight or glucose levels, and no adverse effects were observed in the animals.
  
  
  CONCLUSIONS
  These preclinical findings suggest that clinical PET imaging is a useful tool for early response monitoring in clinical studies.
authors.affiliation: Department of Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Eberhard Karls University Tübingen, Tübingen, Germany. stefan.wiehr@med.uni-tuebingen.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiehr
authors.forename: Oliver
authors.initials: O
authors.lastname: von Ahsen
authors.forename: Lars
authors.initials: L
authors.lastname: Röse
authors.forename: Andre
authors.initials: A
authors.lastname: Mueller
authors.forename: Julia G
authors.initials: JG
authors.lastname: Mannheim
authors.forename: Valerie
authors.initials: V
authors.lastname: Honndorf
authors.forename: Damaris
authors.initials: D
authors.lastname: Kukuk
authors.forename: Gerald
authors.initials: G
authors.lastname: Reischl
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography / Q000379:methods*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C530105:Ccnd1 protein, mouse; D019788:Fluorodeoxyglucose F18; D019938:Cyclin D1; D019859:Proto-Oncogene Proteins c-met; D048049:Extracellular Signal-Regulated MAP Kinases