Abstract 5237: Non-invasive detection of urokinase-type plasminogen activator receptor (uPAR) expression in four human cancer xenograft mouse models using microPET/CT
Authors: Persson Morten , Madsen Jacob , Østergaard Søren , Ploug Michael , Kjær Andreas 
Published: February 2011

Background & Aim

The urokinase-type plasminogen activator receptor (uPAR) has been shown to facilitate cancer cell invasion and metastasis. uPAR is over-expressed in various cancers, including human breast, prostate and colorectal cancer, and these increased levels correlate to poor patient prognosis. With a view to future tailoring of uPAR-targeted therapies and the proven prognostic significance, we have developed an in vivo imaging positron-emission-tomography (PET) agent, which could identify cancer patients at increased risk and whom may benefit from such an adjuvant treatment.

Methods

The peptide antagonist AE1051 was characterized in vivo after DOTA conjugation and radio-labeling with 64Cu, in four different human cancer xenograft mouse models: H727 (lung carcinoid), HT-29 (colorectal carcinoma), A2780 (ovarian carcinoma) and U87MG (glioblastome) with a different expression of uPAR (n=10 mice, 2 tumors/mice). Nude mice carrying the above xenotransplants were injected intravenously with the tracer and a 10 min static PET scan were performed 1, 4.5 and 22 hrs post injection, followed by compute-tomography (CT) scan. Tumors were subsequently removed and their lysates were used to assess uPAR expression levels using standard uPAR ELISA. Another group of mice were PET scanned with 18F-FDG (n=10) and the results were compared with the results obtained with the uPAR tracer. In addition, a separate group of mice were subjected to biodistribution analysis of 64Cu-DOTA-AE105 (n=3 mice) and a mutated non-binding version of the tracer (n=3 mice) using a well-counter, to investigate the uptake in various organs and tissue 4.5 hrs p.i.

Results

A high and specific tumor uptake of 18F-FDG were observed in all four xenograft models but no correlation between uptake and uPAR expression was found (p=0.30, r=0.24). In contrast, a significant correlation was found for 64Cu-DOTA-AE105 tumor uptake and uPAR expression after both 1.0 hr (p=0.01, r=0.53), 4.5 hrs (p=0.0075, r=0.57) and 22 hrs (P&lt;0.0001, r=0.76) across all four cancer xenograft models (n=20 tumors). The specificity of the tracer was validated using a mutated non-binding version of the peptide. A significant decrease in tumor uptake based on well-counter analysis (n=6 tumors) in the U87MG xenograft was found (p=0.028) compared with 64Cu-DOTA-AE105 tumor uptake after 4.5 hrs post injection, thus validating the specificity of the tracer towards uPAR.

Conclusion

Our data demonstrate a significant quantitative correlation between uPAR expression and tumor uptake and thus, that the PET tracer 64Cu-DOTA-AE105 is a promising radiotracer for non-invasive detection of uPAR in different human cancers. The results indicate a different tumor uptake profile compared with standard 18F-FDG and thus additional new tumor-specific information.

1Ploug et al 2001, Biochemistry 40, 12157-12168.

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 5237.