[18F]FLT and [18F]FDG PET for non-invasive treatment monitoring of the nicotinamide phosphoribosyltransferase inhibitor APO866 in human xenografts.

Abstract

INTRODUCTION:

APO866 is a new anti-tumor compound inhibiting nicotinamide phosphoribosyltransferase (NAMPT). APO866 has an anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of this study was non-invasively to study effect of APO866 treatment on [18F]FLT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake.

METHODS:

In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment. Baseline [18F]FLT or [18F]FDG scans were made before treatment and repeated after 24 hours, 48 hours and 7 days. Tumor volume was followed with computed tomography (CT). Tracer uptake was quantified using small animal PET/CT. One hour after iv injection of tracer, static PET scans were performed. Imaging results were compared with Ki67 immunohistochemistry.

RESULTS:

Tumors treated with APO866 had volumes that were 114% (24 h), 128% (48 h) and 130% (Day 7) relative to baseline volumes at Day 0. In the control group tumor volumes were 118% (24 h), 145% (48 h) and 339% (Day 7) relative to baseline volumes Day 0. Tumor volume between the treatment and control group was significantly different at Day 7 (P = 0.001). Compared to baseline, [18F]FLT SUVmax was significantly different at 24 h (P<0.001), 48 h (P<0.001) and Day 7 (P<0.001) in the APO866 group. Compared to baseline, [18F]FDG SUVmax was significantly different at Day 7 (P = 0.005) in the APO866 group.

CONCLUSIONS:

APO866 treatment caused a significant decrease in [18F]FLT uptake 24 and 48 hours after treatment initiation. The early reductions in tumor cell proliferation preceded decrease in tumor volume. The results show the possibility to use [18F]FLT and [18F]FDG to image treatment effect early following treatment with APO866 in future clinical studies.

• Authors: Mette Munk Jensen, Kamille Dumong Erichsen, Camilla Bardram Johnbeck, Fredrik Björkling, Jacob Madsen, Michael Bzorek, Peter Buhl Jensen, Liselotte Højgaard, Maxwell Sehested, Andreas Kjær
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e53410 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23308217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• Antineoplastic Agents
• Dideoxynucleosides
• Fluorine Radioisotopes
• Ki-67 Antigen
• N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
• Piperidines
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• Nicotinamide Phosphoribosyltransferase
• alovudine

Topics

• Acrylamides (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Biological Transport (drug effects)
• Cell Proliferation (drug effects)
• Clinical Trials, Phase II as Topic
• Dideoxynucleosides (metabolism)
• Drug Monitoring (methods)
• Female
• Fluorine Radioisotopes
• Fluorodeoxyglucose F18 (metabolism)
• Gene Expression (drug effects)
• Humans
• Ki-67 Antigen (genetics, metabolism)
• Mice
• Mice, Nude
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, metabolism)
• Ovarian Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Piperidines (pharmacology)
• Positron-Emission Tomography
• Radiography
• Radiopharmaceuticals (metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays