title: New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts.
abstract: The proposition of uPAR as a potential target in cancer therapy is advanced by its predominant expression at the invasive front of colorectal cancer (CRC) and its value as prognostic biomarker for poor survival in this disease. In this study, we provide the first in vivo proof-of-concept for a theranostic approach as treatment modality in a human xenograft colorectal cancer model.
  
  
  METHODS
  A DOTA-conjugated 9-mer high affinity uPAR binding peptide (DOTA-AE105) was radiolabeled with (64)Cu and (177)Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29 cells were inoculated in Nude mice and treated with (177)Lu-DOTA-AE105 once a visible tumor had formed. To evaluate the true effect of the targeted radiotherapy, two controls groups were included in this study, one receiving a (177)Lu-labeled non-binding control peptide and one receiving vehicle. All animals were treated day 0 and 7. A parallel (18)F-FLT PET/CT study was performed on day 0, 1, 3 and 6. Dosimetry calculations were based on a biodistribution study, where organs and tissue of interest were collected 0.5, 1.0, 2.0, 4.0 and 24h post injection of (177)Lu-DOTA-AE105. Toxicity was assessed by recording mouse weight and by H&E staining of kidneys in each treatment group.
  
  
  RESULTS
  uPAR-positive HT-29 xenograft was clearly visualized by PET/CT imaging using (64)Cu-DOTA-AE105. Subsequently, these xenograft transplants were locally irradiated using (177)Lu-DOTA-AE105, where a significant effect on tumor size and the number of uPAR-positive cells in the tumor was found (p<0.05). Evaluations of biodistribution and dosimetry revealed highest accumulation of radioactivity in kidneys and tumor tissue. (18)F-FLT PET/CT imaging study revealed a significant correlation between (18)F-FLT tumor uptake and efficacy of the radionuclide therapy. A histological examination of the kidneys from one animal in each treatment group did not reveal any gross abnormalities and the general performance of all treated animals also showed no indications of radioactivity-induced toxicity.
  
  
  CONCLUSIONS
  These findings document for the first time the in vivo efficacy of an uPAR-targeted radionuclide therapeutic intervention on both tumor size and its content of uPAR expressing cells thus setting the stage for future translation into clinical use.
authors: The Danish-Chinese Center for Proteases and Cancer, Center for Diagnostic Investigations, Rigshospitalet, Copenhagen, Denmark.
authors: Morten
authors: M
authors: Persson
authors: Palle
authors: P
authors: Rasmussen
authors: Jacob
authors: J
authors: Madsen
authors: Michael
authors: M
authors: Ploug
authors: Andreas
authors: A
authors: Kjaer
mesh_terms: D000818:Animals; D001610:Beta Particles / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D015224:Dideoxynucleosides; D005260:Female; D019073:HT29 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D008187:Lutetium / Q000627:therapeutic use*; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D011868:Radioisotopes / Q000627:therapeutic use*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D015224:Dideoxynucleosides; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides; D011868:Radioisotopes; D055293:Receptors, Urokinase Plasminogen Activator; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; C002854:alovudine