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

PLoS One. 2013;8(1):e53410. doi: 10.1371/journal.pone.0053410. Epub 2013 Jan 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Ki-67 Antigen / metabolism
  • Mice
  • Mice, Nude
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Ovarian Neoplasms / diagnostic imaging*
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Piperidines / pharmacology*
  • Positron-Emission Tomography
  • Radiography
  • Radiopharmaceuticals / metabolism*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 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

Grants and funding

Funding came from the National Advanced Technology Foundation, The John and Birthe Meyer Foundation, Danish Medical Research Council, Rigshospitalets Research Foundation, Svend Andersen Foundation, AP Møller Foundation, Novo Nordisk Foundation, Lundbeck Foundation and Danish Cancer Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.