Abstract 4930: Quantitative PET imaging of tissue factor expression using 18F-labeled active site inhibited factor VIIa

Abstract

Abstract Objectives: Tissue factor (TF) is up regulated in many solid tumors and its expression is linked to tumor angiogenesis, invasion, metastasis and prognosis. Hence it would be of clinical relevance if one could assess tumor TF expression status non-invasively. Here we report the development of a new PET tracer for specific imaging of TF using a derivative of factor VII, the natural ligand to TF, labeled with 18F. Methods: Active site inhibited factor VIIa (ASIS) was radiolabeled with N-succinimidyl 4-18F-fluorobenzoate ([18F]SFB) and purified. Nude mice (n=5) with subcutaneous human pancreatic xenograft tumors (BxPC-3) underwent small animal PET/CT imaging 1, 2 and 4 hours after injection of 7.3-9.3 MBq [18F]ASIS (∼37 µg) in 160 µL saline. Mice were euthanized following the last imaging session, and their tumors and major organs were resected for ex vivo gamma well counting. Tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The blocking group (n=3) received 500 µg non-labeled ASIS before injection of [18F]ASIS and was imaged after 4 hours. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by ELISA. Results: The PET images showed high uptake of [18F]ASIS in the tumor regions with a mean uptake of 2.40 ±0.18, 2.56 ±0.20 and 2.54 ±0.27 %ID/g (Mean ±SEM) at 1, 2 and 4 hours after injection of [18F]ASIS and with an average maximum uptake in the tumors of 7.08 ±0.72 %ID/g at 4 hours. In comparison, the muscle uptake was 0.19 ±0.01 %ID/g at 4 hours. At 4 hours the tumors had the highest uptake of any organ. Blocking with cold ASIS significantly reduced the uptake of [18F]ASIS from 2.51 ±0.06 to 1.29 ±0.07 %ID/g (p<0.001). Importantly, the uptake of [18F]ASIS measured in vivo by PET imaging correlated (r=0.72, p<0.02) with TF expression at the protein level measured ex vivo in tumor homogenates by ELISA. Conclusion: PET/CT imaging with [18F]ASIS can be used for specific, non-invasive imaging of TF expression. Research Support: This work was supported by at grant from the Danish National Advanced Technology Foundation. Citation Format: Carsten H. Nielsen, Maria Erlandsson, Mette M. Jensen, Jacob Madsen, Lars C. Petersen, Andreas Kjaer. Quantitative PET imaging of tissue factor expression using 18F-labeled active site inhibited factor VIIa. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4930. doi:10.1158/1538-7445.AM2014-4930