Abstract 5315: PET imaging with the proliferation tracer 18F-FLT as early, non-invasive predictor of everolimus effect on tumor growth: Studies in human neuroendocrine tumor xenografts in mice

Abstract

Abstract Background and aim: Everolimus (RAD001), an oral mTOR inhibitor has shown promising results in the treatment of several types of cancer including neuroendocrine tumors. With the expanding numbers of clinical treatment protocols there is a need for early, non-invasive predictors of treatment response. We hypothesized that PET imaging with the proliferation tracer 3′-Deoxy-3′-[(18)F]fluorothymidine (FLT) could serve as such a predictor. Therefore, we studied in human neuroendocrine tumor xenografts in mice whether PET imaging with FLT could predict, at an early time-point, the effect of everolimus on tumor growth. Methods: In vivo uptake of FLT in human neuroendocrine xenografts (H727) in mice was studied at baseline when tumors were on average 140 mm3. The mice were randomized into two groups. One group of mice (n=10 tumors) were treated with daily i.p. injections of everolimus (5 mg/kg) for 10 days while another group of mice (n=10 tumors) served as control and was given the same volume of vehicle i.p. The mice were FLT scanned at day 0, 1, 3, 7 and 10. Each PET scan was acquired over 15 min 1 h after injection in a tail vein of 10 MBq FLT. In addition, a CT-scan was performed for calculation of tumor volume. The tumors were defined on PET/CT images and FLT uptake was calculated as mean standardized uptake values (SUV). Results: Everolimus treated mice showed a clear reduction in tumor growth compared to the vehicle group at day 7 and 10 (P<0.0001). At day 7 the relative tumor volumes (day 7/day 0) were 1.78±0.10 in the everolimus group and 2.77±0.11 (407 mm3) in the control group. At day 10 the relative tumor volumes (day 10/day 0) were 2.17±0.15 (304 mm3) in the everolimus group and 3.50±0.13 (518 mm3) in the vehicle group. The relative FLT SUV value on day 10 showed significantly reduced uptake (P=0.003) in the everolimus group (0.91±0.06) compared to the control group (1.16±0.04). In the everolimus group FLT uptake at day 3 predicted relative tumor size both at day 7 (R2=0.53; P=0.017) and day 10 (R2=0.60; P=0.024). FLT uptake at day 1 also predicted tumor growth, although only borderline significant, at day 3 (R2=0.38; P=0.060), 7 (R2=0.39; P=0.055) and 10 (R2=0.45; P=0.069). Conclusion: FLT-PET imaging as early as 1 or 3 days after treatment initiation with everolimus predicts neuroendocrine tumor growth over the first 10 days of treatment. We suggest that FLT-PET is a promising tool for early prediction of effect of everolimus in patients with neuroendocrine tumors and may be used for tailoring therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5315. doi:10.1158/1538-7445.AM2011-5315