title: Differential (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine PET responses to pharmacologic inhibition of the c-MET receptor in preclinical tumor models.
abstract: The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling.
  
  
  METHODS
  Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting.
  
  
  RESULTS
  Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 μM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively.
  
  
  CONCLUSIONS
  While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Donna S
authors.initials: DS
authors.lastname: Dorow
authors.forename: Susan
authors.initials: S
authors.lastname: Jackson
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bogatyreva
authors.forename: David
authors.initials: D
authors.lastname: Binns
authors.forename: Richard
authors.initials: R
authors.lastname: Young
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arango
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000077547:Crizotinib; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D015224:Dideoxynucleosides; D051272:Glucose Transporter Type 1; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D019788:Fluorodeoxyglucose F18; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met; D005947:Glucose; C002854:alovudine