Quantitative PET of human urokinase-type plasminogen activator receptor with 64Cu-DOTA-AE105: implications for visualizing cancer invasion.
Expression levels of the urokinase-type plasminogen activator receptor (uPAR) represent an established biomarker for poor prognosis in a variety of human cancers. The objective of the present study was to explore whether noninvasive PET can be used to perform a quantitative assessment of expression levels of uPAR across different human cancer xenograft models in mice and to illustrate the clinical potential of uPAR PET in future settings for individualized therapy.


METHODS
To accomplish our objective, a linear, high-affinity uPAR peptide antagonist, AE105, was conjugated with DOTA and labeled with (64)Cu ((64)Cu-DOTA-AE105). Small-animal PET was performed in 3 human cancer xenograft mice models, expressing different levels of human uPAR, and the tumor uptake was correlated with the uPAR expression level determined by uPAR enzyme-linked immunosorbent assay. The tumor uptake pattern of this tracer was furthermore compared with (18)F-FDG uptake, and finally the correlation between sensitivity toward 5-fluorouracil therapy and uPAR expression level was investigated.


RESULTS
The uPAR-targeting PET tracer was produced in high purity and with high specific radioactivity. A significant correlation between tumor uptake of (64)Cu-DOTA-AE105 and uPAR expression was found (R(2) = 0.73; P < 0.0001) across 3 cancer xenografts, thus providing a strong argument for specificity. A significantly different uptake pattern of (64)Cu-DOTA-AE105, compared with that of (18)F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using (64)Cu-DOTA-AE105 PET. Furthermore, a significant correlation between baseline uPAR expression and sensitivity toward 5-fluorouracil was revealed, thus illustrating the possible potentials of uPAR PET in a clinical setting.


CONCLUSIONS
Our results clearly demonstrate that the peptide-based PET tracer (64)Cu-DOTA-AE105 enables the noninvasive quantification of uPAR expression in tumors in vivo, thus emphasizing its potential use in a clinical setting to detect invasive cancer foci and for individualized cancer therapy.
The Danish Chinese Center for Proteases and Cancer, Copenhagen, Denmark.
Morten
M
Persson
Jacob
J
Madsen
Søren
S
Østergaard
Mette Munk
MM
Jensen
Jesper Tranekjær
JT
Jørgensen
Karina
K
Juhl
Charlotte
C
Lehmann
Michael
M
Ploug
Andreas
A
Kjaer
D000818:Animals; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D003301:Copper Radioisotopes; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D051379:Mice; D064847:Multimodal Imaging; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014057:Tomography, X-Ray Computed
D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides; D055293:Receptors, Urokinase Plasminogen Activator; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid