Abstract 5308: PET imaging of hypoxia with [64]Cu-ATSM in human ovarian cancer: Comparison of xenografts in mice and rats
Authors: Joergensen Jesper T. , Madsen Jacob , Kjaer Andreas 
Published: June 2012

Abstract
Aim: [64]Cu-ATSM (Cu-ATSM) is a promising hypoxia tracer for PET imaging. However, relatively low uptake is seen in human xenografts in mice compared to patients. We hypothesized that human xenografts in rats might render higher uptake and be a better and clinically more relevant model for study of hypoxia in tumors. Accordingly, we compared hypoxia imaging in human ovarian cancer xenografts implanted in nude mice and nude rats. In addition, the hypoxia tracer accumulation was compared to that of [18]F-FDG (FDG), as well as to gene expression of HIF-1α.
Methods: All animals had 10⁁7 A2780 human ovarian cancer cells inoculated into each flank. After 2-3 weeks all animal were subjected to a FDG scan 1 hr post injection. The following day each animal were PET scanned again, both 1hr and 22 hrs after injection of Cu-ATSM. Immediately after the 22 hr scan the animals were euthanized and the tumors resected. Total RNA was isolated from whole tumor tissue extracts (mice xenografts n=12; rat xenografts n=8) and gene expression measurements performed, using quantitative real-time PCR. PET data were reconstructed using the MAP algorithm, regions of interest drawn on the PET images and tracer uptake (SUV) calculated. Finally, correlation between tracer uptake and gene expression was analyzed by linear regression.
Results: Cu-ATSM uptake in A2780 xenografts from mice had average SUVmean value of 0.32±0.02 and 0.30±0.01, at 1 and 22 hrs post injection, respectively. Compared to this, the xenografts from rats had an average SUVmean value of 1.73±0.09 1 hr post injection, and like in the mice, had a small decrease to 1.35±0.05 at 22 hrs post injection. The same pattern was seen for the Cu-ATSM SUVmax values decreasing from 0.71±0.04 to 0.64±0.02 in mice and from 3.75±0.09 to 3.39±0.20 in rats. The average SUVmean and SUVmax values for FDG 1 hr post injection was 0.38±0.02 and 0.79±0.03 in mice and 3.27±0.34 and 6.83±0.80 in rats, respectively. No correlation between SUV for Cu-ATSM and FDG was seen. For the mice, gene expression of HIF-1α showed a positive correlation with SUVmean values of Cu-ATSM both 1 and 22 hrs post injection (r=0.77, p=0.004; r=0.65, p=0.02, respectively). In the same way HIF-1α also correlated with SUVmax 1 hr post injection (r=0.60, p=0.04). No correlations were found between HIF-1α and FDG SUV values. Gene expression measurements of tumors from rats are currently being conducted.
Conclusion: A 5-6 fold higher uptake of Cu-ATSM was seen in human ovarian cancer xenograft tumors when implanted in nude rats compared to nude mice. The SUV values in rats was of the same magnitude as seen in patients making the rat model promising as a tool for further translational research on hypoxia imaging. The Cu-ATSM tumor uptake showed good correlation with gene expression of HIF-1α but did not correlate with FDG uptake. This indicates that Cu-ATSM is indeed reflecting hypoxia and that information is different than that obtained with FDG PET.
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 5308. doi:10.1158/1538-7445.AM2011-5308