TY - JOUR
T1 - Quantitative PET of human urokinase-type plasminogen activator receptor with 64Cu-DOTA-AE105
T2 - implications for visualizing cancer invasion
AU - Persson, Morten
AU - Madsen, Jacob
AU - Østergaard, Søren
AU - Jensen, Mette Munk
AU - Jørgensen, Jesper Tranekjær
AU - Juhl, Karina
AU - Lehmann, Charlotte
AU - Ploug, Michael
AU - Kjaer, Andreas
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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 64Cu ( 64Cu-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 18F-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 64Cu-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 64Cu-DOTA-AE105, compared with that of 18F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using 64Cu-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. Conclusion: Our results clearly demonstrate that the peptide-based PET tracer 64Cu-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.
AB - 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 64Cu ( 64Cu-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 18F-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 64Cu-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 64Cu-DOTA-AE105, compared with that of 18F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using 64Cu-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. Conclusion: Our results clearly demonstrate that the peptide-based PET tracer 64Cu-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.
KW - Animals
KW - Cell Transformation, Neoplastic
KW - Colorectal Neoplasms
KW - Copper Radioisotopes
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - HT29 Cells
KW - Heterocyclic Compounds, 1-Ring
KW - Humans
KW - Mice
KW - Neoplasm Invasiveness
KW - Oligopeptides
KW - Positron-Emission Tomography
KW - Positron-Emission Tomography and Computed Tomography
KW - Radiochemistry
KW - Receptors, Urokinase Plasminogen Activator
U2 - 10.2967/jnumed.110.083386
DO - 10.2967/jnumed.110.083386
M3 - Journal article
C2 - 22213823
SN - 0161-5505
VL - 53
SP - 138
EP - 145
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 1
ER -
