title: Preclinical efficacy of the anti-hepatocyte growth factor antibody ficlatuzumab in a mouse brain orthotopic glioma model evaluated by bioluminescence, PET, and MRI.
abstract: OBJECTIVE
  Ficlatuzumab is a novel therapeutic agent targeting the hepatocyte growth factor (HGF)/c-MET pathway. We summarize extensive preclinical work using this agent in a mouse brain orthotopic model of glioblastoma.
  
  
  METHODS
  Sequential experiments were done using eight- to nine-week-old nude mice injected with 3 × 10(5) U87 MG (glioblastoma) cells into the brain. Evaluation of ficlatuzumab dose response for this brain tumor model and comparison of its response to ficlatuzumab and to temozolamide were conducted first. Subsequently, various small-animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and MRI, were used with a U87 MG-Luc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to noninvasively assess tumor growth and response to therapy. ANOVA was conducted to evaluate for significant differences in the response.
  
  
  RESULTS
  There was a survival benefit with ficlatuzumab alone or in combination with temozolamide. BLI was more sensitive than PET in detecting tumor cells. Fluoro-D-thymidine (FLT) PET provided a better signal-to-background ratio than 2[(18)F]fluoro-2-deoxy-d-glucose (FDG) PET. In addition, both BLI and FLT PET showed significant changes over time in the control group as well as with response to therapy. MRI does not disclose any time-dependent change. Also, the MRI results showed a temporal delay in comparison to the BLI and FLT PET findings, showing similar results one drug cycle later.
  
  
  CONCLUSIONS
  Targeting the HGF/c-MET pathway with the novel agent ficlatuzumab appears promising for the treatment of glioblastoma. Various clinically applicable imaging modalities including FLT, PET, and MRI provide reliable ways of assessing tumor growth and response to therapy. Given the clinical applicability of these findings, future studies on patients with glioblastoma may be appropriate.
authors: Authors' Affiliations: Molecular Imaging Program, Department of Radiology, System Medicine, Department of Pediatrics, Division of Neuropathology, Department of Pathology, Merck Research Laboratories, Palo Alto, California; AVEO Pharmaceuticals Inc., Cambridge, Massachusettes; and Bio-X Program, Department of Bioengineering, Department of Materials Science & Engineering, Stanford University, Stanford.
authors: Erik S
authors: ES
authors: Mittra
authors: Hua
authors: H
authors: Fan-Minogue
authors: Frank I
authors: FI
authors: Lin
authors: Jason
authors: J
authors: Karamchandani
authors: Venkataraman
authors: V
authors: Sriram
authors: May
authors: M
authors: Han
authors: Sanjiv S
authors: SS
authors: Gambhir
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D019275:Radiopharmaceuticals; D017228:Hepatocyte Growth Factor; C583360:ficlatuzumab
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