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

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

Mette Munk Jensen  1 , Kamille Dumong Erichsen, Camilla Bardram Johnbeck, Fredrik Björkling, Jacob Madsen, Michael Bzorek, Peter Buhl Jensen, Liselotte Højgaard, Maxwell Sehested, Andreas Kjær
Affiliations

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

Mette Munk Jensen et al. PLoS One. 2013.

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.

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Conflict of interest statement

Competing Interests: The following co-authors have conflict of interests: Peter Buhl Jensen: Ownership Interests and Employment in Topotarget A/S. Maxwell Sehested: Ownership Interests and Employment in Topotarget A/S. Fredrik Björkling: Employment in Topotarget A/S. Kamille Dumong Erichsen: Employment in Topotarget A/S. All other authors have no conflict of interests. The authors do, to the best of their knowledge, not have any patent regarding APO866. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Chemical structure of the nicotinamide phosphoribosyltransferase inhibitor APO866.
Figure 2
Figure 2. Determination of tumor volume by microCT and caliper.
Comparison of tumor weight and tumor volume determined by microCT and caliper respectively (N = 34–35 tumors). An identity line is included in the graph. After the last PET scan the tumors were excised and weighed and tumor weight was correlated with the microCT determined tumor volume measured on Day 7 (P<0.001, r2 = 0.98) and caliper determined tumor volume measured on Day 7 (P<0.001; r2 = 0.87).
Figure 3
Figure 3. Tumor growth of APO866 and vehicle treated A2780 xenografts.
The effects of APO866 on the growth of A2780 tumor xenografts were measured. Tumor volume was determined by microCT. Mice were treated with APO866 (15 mg/kg) or vehicle ip twice daily for 7 days. N = 22 tumors in treatment group and N = 18 in control group. Values are stated as mean±SEM.
Figure 4
Figure 4. [18F]FLT and [18F]FDG uptake after treatment of A2780 xenografts with APO866.
[18F]FLT and [18F]FDG uptake assessed by SUVmean and SUVmax at baseline and following treatment with APO866. Mice were treated with APO866 (15 mg/kg) or vehicle ip twice daily for 7 days. N = 6 tumors in [18F]FLT control group, N = 10 tumors in [18F]FLT treatment group, N = 12 tumors in [18F]FDG control group and N = 12 tumors in [18F]FDG treatment group. The two graphs at left show data from the [18F]FLT experiments and the two graphs at right show data from the [18F]FDG experiments. *) P<0.05, **) P<0.01, ***) P<0.001 versus baseline in same treatment group. Values are stated as mean±SEM.
Figure 5
Figure 5. PET/CT images.
Combined PET/CT images of a mouse treated with APO866 and scanned with [18F]FLT (upper panel) and a mouse treated with APO866 and scanned with [18F]FDG (lower panel).
Figure 6
Figure 6. Correlation between SUVmax and tumor growth.
Tumor growth assessed by ratio Day 7/baseline compared to uptake of [18F]FLT (upper panels) and [18F]FDG (lower panels) at 24 h (right panels), 48 h (middle panels) and 7 days (left panels). N = 6 tumors in [18F]FLT control group, N = 10 tumors in [18F]FLT treatment group, N = 12 tumors in [18F]FDG control group and N = 12 tumors in [18F]FDG treatment group.
Figure 7
Figure 7. Correlation between Ki67 expression and [18F]FLT uptake. A
Correlation of Ki67 protein expression measured by immunohistochemistry with [18F]FLT uptake measured as SUVmean (upper panel). Lower panel compares Ki67 protein expression in the APO866 (N = 10) and control group (N = 6) at the end of the 7 day treatment period. Values are stated as mean±SEM. B Representative images of Ki67 stains of an APO866 treated (left) and a control (right) mouse in 40×magnification.
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