title: Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma.
abstract: Glioblastoma is one of the most malignant types of human cancer, and the prognosis is poor. The development and validation of novel molecular imaging biomarkers has the potential to improve tumor detection, grading, risk stratification, and treatment monitoring of gliomas. The aim of this study was to explore the potential of PET imaging of the urokinase-type plasminogen activator receptor (uPAR) in glioblastoma.
  
  
  METHODS
  The uPAR messenger RNA expression of tumors from 19 glioblastoma patients was analyzed, and a cell culture derived from one of these patients was used to establish an orthotopic xenograft model of glioblastoma. Tumor growth was monitored using bioluminescence imaging. Five to six weeks after inoculation, all mice were scanned with small-animal PET/CT using two new uPAR PET ligands ((64)Cu-NOTA-AE105 and (68)Ga-NOTA-AE105) and, for comparison, O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of (64)Cu-NOTA-AE105 was confirmed by alignment of hematoxylin- and eosin-stained and uPAR immunohistochemistry-stained slides of the brain with the activity distribution as determined using autoradiography.
  
  
  RESULTS
  uPAR expression was found in all 19 glioblastoma patient tumors, and high expression of uPAR correlated with decreased overall survival (P = 0.04). Radiolabeling of NOTA-AE105 with (64)Cu and (68)Ga was straightforward, resulting in a specific activity of approximately 20 GBq/μmol and a radiochemical purity of more than 98% for (64)Cu-NOTA-AE105 and more than 97% for (68)Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both (68)Ga-NOTA-AE105 and (64)Cu-NOTA-AE105. Absolute uptake in tumor was higher for (18)F-FET (3.5 ± 0.8 percentage injected dose [%ID]/g) than for (64)Cu-NOTA-AE105 (1.2 ± 0.4 %ID/g) or (68)Ga-NOTA-AE105 (0.4 ± 0.1 %ID/g). A similar pattern was observed in background brain tissue, where uptake was 1.9 ± 0.1 %ID/g for (18)F-fluorothymidine, compared with 0.05 ± 0.01 %ID/g for (68)Ga-NOTA-AE105 and 0.11 ± 0.02 %ID/g for (64)Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both (68)Ga-NOTA-AE105 (7.6 ± 2.1, P < 0.05) and (64)Cu-NOTA-AE105 (10.6 ± 2.3, P < 0.01) than for (18)F-FET PET (1.8 ± 0.3). Autoradiography of brain slides confirmed that the accumulation of (64)Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells.
  
  
  CONCLUSIONS
  On the basis of our translational study, uPAR PET may be a highly promising imaging biomarker for glioblastoma. Further clinical exploration of uPAR PET in glioblastoma is therefore justified.
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Persson
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark Department of Radiation Biology, Finsen Center, Rigshospitalet, Copenhagen, Denmark; and.
authors.forename: Mette K
authors.initials: MK
authors.lastname: Nedergaard
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Brandt-Larsen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Skovgaard
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Jørgensen
authors.affiliation: Department of Radiation Biology, Finsen Center, Rigshospitalet, Copenhagen, Denmark; and.
authors.forename: Signe R
authors.initials: SR
authors.lastname: Michaelsen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.affiliation: Department of Oncology, Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lassen
authors.affiliation: Department of Radiation Biology, Finsen Center, Rigshospitalet, Copenhagen, Denmark; and.
authors.forename: Hans S
authors.initials: HS
authors.lastname: Poulsen
authors.affiliation: Department of Clinical Physiology, Nuclear Medicine, and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark akjaer@sund.ku.dk.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjaer
mesh_terms: D000328:Adult; D000818:Animals; D001345:Autoradiography; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000000981:diagnostic imaging*; D002478:Cells, Cultured; D003301:Copper Radioisotopes; D005260:Female; D005909:Glioblastoma / Q000000981:diagnostic imaging*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000096:biosynthesis; D019275:Radiopharmaceuticals; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D003301:Copper Radioisotopes; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D055293:Receptors, Urokinase Plasminogen Activator
keywords: PET; PET/CT; glioblastoma; survival; translational; urokinase-type