Abstract 5220: Early prediction of tumor response to APO866 treatment with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography in human ovary cancer xenografts in mice

Abstract

Abstract Introduction: APO866 is a new anti-tumor compound found to inhibit nicotinamide phosphoribosyltransferase (NAMPT), an enzyme involved in the biosynthesis of NAD. The compound has anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3′-deoxy-3′-[18F]fluorothymidine (FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to evaluate if FLT positron emission tomography (PET) may be used to monitor early anti-proliferative effects of APO866. Methods: In vivo uptake of FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment (15 mg/kg ip twice daily for 7 days) was initiated. Baseline FLT scans were made before either APO866 (n=10 tumors) or vehicle (n=6 tumors) was injected and repeated after 24 hours (2 treatments), 48 hours (4 treatments) and 7 days (14 treatments). Tumor volume was followed with computed tomography (CT) during the experiment. FLT uptake was quantified using small animal PET/CT. One hour after iv injection of 10 MBq FLT, static PET scans were performed for 10 minutes and region of interests (ROIs) covering whole tumors were defined on PET/CT images for calculation of standard uptake values (SUV). Comparison within treatment groups was performed using paired t-tests and between control and APO866 groups with unpaired t-tests. All p-values were corrected for multiple comparisons using the Bonferroni algorithm. P<0.05 was considered significant. Results: Tumors treated with APO866 had volumes that were 122% (24h), 129 % (48h) and 88% (day 7) relative to baseline volumes day 0. In the control group tumor volumes were 123% (24h), 150% (48h) and 318% (day 7) relative to baseline volumes day 0. Tumor volume between groups were significantly different at day 7 (P=0.006). APO866 treatment caused significant decrease in uptake of FLT at 24 hours (−23%; P<0.001), 48 hours (−29%; P<0.001) and day 7 (−25%; P=0.0013) after treatment start compared to baseline uptake. In the control group uptake of FLT did not change. Conclusions: APO866 treatment caused a significant decrease in FLT uptake 24 and 48 hours after injection of first dose. The early reductions in tumor cell proliferation preceded decrease in tumor volume on day 7. Our data indicate that FLT PET is promising for early non-invasive assessment of APO866 anti-tumor effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5220.