RT Journal Article
SR Electronic
T1 Differential <sup>18</sup>F-FDG and 3′-Deoxy-3′-<sup>18</sup>F-Fluorothymidine PET Responses to Pharmacologic Inhibition of the c-MET Receptor in Preclinical Tumor Models
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1261
OP 1267
DO 10.2967/jnumed.110.086967
VO 52
IS 8
A1 Carleen Cullinane
A1 Donna S. Dorow
A1 Susan Jackson
A1 Benjamin Solomon
A1 Ekaterina Bogatyreva
A1 David Binns
A1 Richard Young
A1 Maria E. Arango
A1 James G. Christensen
A1 Grant A. McArthur
A1 Rodney J. Hicks
YR 2011
UL http://jnm.snmjournals.org/content/52/8/1261.abstract
AB 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 18F-FDG PET is well established, 3′-deoxy-3′-18F-fluorothymidine (18F-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 18F-FDG and 18F-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 3H-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 18F-FDG uptake (P &lt; 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline 18F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, 18F-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 18F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively. Conclusion: While the results provide a strong rationale to investigate the use of 18F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, 18F-FDG PET may be a less robust marker.