uPAR Targeted Radionuclide Therapy with 177Lu-DOTA-AE105 Inhibits Dissemination of Metastatic Prostate Cancer
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The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an anti-metastatic effect of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR PET imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific activity: a uPAR-targeting probe (177Lu-DOTA-AE105) and a non-binding control (177Lu-DOTA-AE105mut) . Western Blot and uPAR ELISA confirmed high expression levels of the target uPAR in PC-3M-LUC2.luc cells and cell binding studies using 177Lu-DOTA-AE105 resulted in a specific binding with an IC50-value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and non-targeted 177Lu groups (p<0.05) using bioluminescence imaging. Moreover, we found a significant longer metastatic-free survival, with 65% of all mice without any disseminated metastatic lesions present at 65 days after first treatment dose (p=0.047). In contrast, only 30% of all mice in the combined control groups treated with 177Lu-DOTA-AE105mut or vehicle were without metastatic lesions. No treatment-induce toxicity was observed during the study as evaluated by observing animal weight and H&E staining of kidney tissue (dose-limiting organ). Finally, uPAR PET imaging using 64Cu-DOTA-AE105 detected all small-disseminated metastatic foci when compared with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of metastatic lesions in a human metastatic prostate cancer model. Furthermore did we provide the first evidence of the potential for identification of small metastatic lesions using uPAR PET imaging in disseminated prostate cancer, illustrating the promising strategy of uPAR theranostics in prostate cancer.
|Number of pages||11|
|Publication status||Published - 4 Aug 2014|