Abstract 5217: Evaluation of the therapeutic efficacy of MEK inhibitor (TAK-733) using [18F]FDG-PET in the human lung xenograft model A549

Abstract

Abstract Introduction: TAK-733 is a novel, potent, selective, non-ATP competitive, allosteric inhibitor of MEK kinase, which has a potential to inhibit cancer proliferation and survival. [18F]Fluorodeoxyglucose ([18F]FDG) is an imaging biomarker for glucose metabolism detectable using positron emission tomography (PET) and widely used in clinical cancer diagnosis and is increasingly used to assess response to anti-cancer therapy. The aim of this study was to evaluate the therapeutic efficacy of TAK-733 using [18F]FDG-PET in nude rats bearing A549 (human lung carcinoma) xenografts. Methods: A549 tumor fragments were subcutaneously implanted in female RNU nude rats. Treatments began when the mean estimated tumor mass for all groups was 250mg (Day 1). TAK-733 was orally administered at 0 (vehicle), 1, 3 and 10 mg/kg daily for two weeks (n = 8 / group). PET scans were performed before treatment (Day 0) and on Days 2, 4, 7, 10 and 14. PET image acquisition was performed for 13 min at 1.5 hr after [18F]FDG injection (400 μCi). Tracer accumulations in tumor tissue were quantified as mean standard uptake value (SUVmean) and percentage of injected dose (%ID). Results: TAK-733 showed dose-dependent inhibition of tumor growth and [18F]FDG uptake in tumor tissue. TAK-733, at 10mg/kg, produced a statistically significant difference in tumor mass (Day 14) compared to the vehicle group (31% T/C) and in SUVmean (Day 2) compared to the vehicle group. The statistical significance for the 10mg/kg did not persist however, and was only observed at a single time point for tumor mass and SUVmean. However, a significant response in SUVmean (Day 2) occurred before significant tumor growth inhibition (Day 14). In this treatment group, the SUVmean value on Day 2 (1.38 ± 0.26) was lower than that observed at pre-treatment, Day 0 (1.60 ± 0.30), and statistically lower compared to the SUVmean values in the vehicle (1.54 ± 0.46) and 1mg/kg groups (1.53 ± 0.29) on Day 2. The SUVmean value in the vehicle and 1 and 3 mg/kg groups showed an increase over time. On Day 14, the SUVmean value at 10 mg/kg (1.45 ± 0.33) was statistically significantly lower compared to the vehicle group (2.16 ± 0.33). TAK-733 produced a dose-dependent %ID response. 10mg/kg TAK-733 produced the lowest %ID for every imaging time point, while the vehicle group had the highest %ID at every imaging time point. There were no statistically significant differences in %ID response. However, %ID did not show statistically significant decreased values compared to the vehicle group, suggesting that SUVmean may be a more sensitive parameter for [18F]FDG uptake than %ID. Conclusion: [18F]FDG-PET enabled an early indication of later tumor growth in response to TAK-733 treatment in this model. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5217.