Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma

Morten Persson; Mette K Nedergaard; Malene Brandt-Larsen; Dorthe Skovgaard; Jesper T Jørgensen; Signe R Michaelsen; Jacob Madsen; Ulrik Lassen; Hans S Poulsen; Andreas Kjaer

doi:10.2967/jnumed.115.161703

Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma

Morten Persson, Mette K Nedergaard, Malene Brandt-Larsen, Dorthe Skovgaard, Jesper T Jørgensen, Signe R Michaelsen, Jacob Madsen, Ulrik Lassen, Hans S Poulsen, Andreas Kjaer

17 Citations (Scopus)

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 (⁶⁴Cu-NOTA-AE105 and 68Ga-NOTA-AE105) and, for comparison, O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of ⁶⁴Cu-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 5 0.04). Radiolabeling of NOTA-AE105 with 64Cu and 68Ga was straightforward, resulting in a specific activity of approximately 20 GBq/?mol and a radiochemical purity of more than 98% for ⁶⁴Cu-NOTA-AE105 and more than 97% for 68Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both 68Ga-NOTA-AE105 and ⁶⁴Cu-NOTA-AE105. Absolute uptake in tumor was higher for 18F-FET (3.5 ± 0.8 percentage injected dose [%ID]/g) than for ⁶⁴Cu-NOTA-AE105 (1.2 ± 0.4 %ID/g) or 68Ga-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 18F-fluorothymidine, compared with 0.05 ± 0.01 %ID/g for 68Ga-NOTA-AE105 and 0.11 ± 0.02 %ID/g for ⁶⁴Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both 68Ga-NOTA-AE105 (7.6 ± 2.1, P , 0.05) and ⁶⁴Cu-NOTA-AE105 (10.6 ± 2.3, P , 0.01) than for 18F-FET PET (1.8 ± 0.3). Autoradiography of brain slides confirmed that the accumulation of ⁶⁴Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells. Conclusion: 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.

Original language	English
Journal	Journal of Nuclear Medicine
Volume	57
Issue number	2
Pages (from-to)	272-278
Number of pages	7
ISSN	0161-5505
DOIs	https://doi.org/10.2967/jnumed.115.161703
Publication status	Published - 1 Feb 2016

Keywords

Adult
Animals
Autoradiography
Biomarkers, Tumor
Brain Neoplasms
Cells, Cultured
Copper Radioisotopes
Female
Glioblastoma
Humans
Male
Mice
Middle Aged
Positron-Emission Tomography
RNA, Messenger
Radiopharmaceuticals
Receptors
Survival Analysis
Xenograft Model Antitumor Assays
Urokinase Plasminogen Activator

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{22da32d0db064e1aa58781253b584464,

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 (64Cu-NOTA-AE105 and 68Ga-NOTA-AE105) and, for comparison, O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of 64Cu-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 5 0.04). Radiolabeling of NOTA-AE105 with 64Cu and 68Ga was straightforward, resulting in a specific activity of approximately 20 GBq/?mol and a radiochemical purity of more than 98% for 64Cu-NOTA-AE105 and more than 97% for 68Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both 68Ga-NOTA-AE105 and 64Cu-NOTA-AE105. Absolute uptake in tumor was higher for 18F-FET (3.5 ± 0.8 percentage injected dose [%ID]/g) than for 64Cu-NOTA-AE105 (1.2 ± 0.4 %ID/g) or 68Ga-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 18F-fluorothymidine, compared with 0.05 ± 0.01 %ID/g for 68Ga-NOTA-AE105 and 0.11 ± 0.02 %ID/g for 64Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both 68Ga-NOTA-AE105 (7.6 ± 2.1, P , 0.05) and 64Cu-NOTA-AE105 (10.6 ± 2.3, P , 0.01) than for 18F-FET PET (1.8 ± 0.3). Autoradiography of brain slides confirmed that the accumulation of 64Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells. Conclusion: 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.",

keywords = "Adult, Animals, Autoradiography, Biomarkers, Tumor, Brain Neoplasms, Cells, Cultured, Copper Radioisotopes, Female, Glioblastoma, Humans, Male, Mice, Middle Aged, Positron-Emission Tomography, RNA, Messenger, Radiopharmaceuticals, Receptors, Survival Analysis, Xenograft Model Antitumor Assays, Urokinase Plasminogen Activator",

author = "Morten Persson and Nedergaard, {Mette K} and Malene Brandt-Larsen and Dorthe Skovgaard and J{\o}rgensen, {Jesper T} and Michaelsen, {Signe R} and Jacob Madsen and Ulrik Lassen and Poulsen, {Hans S} and Andreas Kjaer",

note = "{\textcopyright} 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.",

year = "2016",

month = feb,

day = "1",

doi = "10.2967/jnumed.115.161703",

language = "English",

volume = "57",

pages = "272--278",

journal = "Journal of Nuclear Medicine",

issn = "0161-5505",

publisher = "Society of Nuclear Medicine",

number = "2",

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TY - JOUR

T1 - Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma

AU - Persson, Morten

AU - Nedergaard, Mette K

AU - Brandt-Larsen, Malene

AU - Skovgaard, Dorthe

AU - Jørgensen, Jesper T

AU - Michaelsen, Signe R

AU - Madsen, Jacob

AU - Lassen, Ulrik

AU - Poulsen, Hans S

AU - Kjaer, Andreas

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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 (64Cu-NOTA-AE105 and 68Ga-NOTA-AE105) and, for comparison, O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of 64Cu-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 5 0.04). Radiolabeling of NOTA-AE105 with 64Cu and 68Ga was straightforward, resulting in a specific activity of approximately 20 GBq/?mol and a radiochemical purity of more than 98% for 64Cu-NOTA-AE105 and more than 97% for 68Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both 68Ga-NOTA-AE105 and 64Cu-NOTA-AE105. Absolute uptake in tumor was higher for 18F-FET (3.5 ± 0.8 percentage injected dose [%ID]/g) than for 64Cu-NOTA-AE105 (1.2 ± 0.4 %ID/g) or 68Ga-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 18F-fluorothymidine, compared with 0.05 ± 0.01 %ID/g for 68Ga-NOTA-AE105 and 0.11 ± 0.02 %ID/g for 64Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both 68Ga-NOTA-AE105 (7.6 ± 2.1, P , 0.05) and 64Cu-NOTA-AE105 (10.6 ± 2.3, P , 0.01) than for 18F-FET PET (1.8 ± 0.3). Autoradiography of brain slides confirmed that the accumulation of 64Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells. Conclusion: 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.

AB - 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 (64Cu-NOTA-AE105 and 68Ga-NOTA-AE105) and, for comparison, O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). One MRI scan was obtained for each mouse to confirm tumor location. The uPAR specificity of 64Cu-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 5 0.04). Radiolabeling of NOTA-AE105 with 64Cu and 68Ga was straightforward, resulting in a specific activity of approximately 20 GBq/?mol and a radiochemical purity of more than 98% for 64Cu-NOTA-AE105 and more than 97% for 68Ga-NOTA-AE105. High image contrast resulting in clear tumor delineation was found for both 68Ga-NOTA-AE105 and 64Cu-NOTA-AE105. Absolute uptake in tumor was higher for 18F-FET (3.5 ± 0.8 percentage injected dose [%ID]/g) than for 64Cu-NOTA-AE105 (1.2 ± 0.4 %ID/g) or 68Ga-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 18F-fluorothymidine, compared with 0.05 ± 0.01 %ID/g for 68Ga-NOTA-AE105 and 0.11 ± 0.02 %ID/g for 64Cu-NOTA-AE105. The result was a significantly higher tumor-to-background ratio for both 68Ga-NOTA-AE105 (7.6 ± 2.1, P , 0.05) and 64Cu-NOTA-AE105 (10.6 ± 2.3, P , 0.01) than for 18F-FET PET (1.8 ± 0.3). Autoradiography of brain slides confirmed that the accumulation of 64Cu-NOTA-AE105 corresponded well with uPAR-positive cancer cells. Conclusion: 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.

KW - Adult

KW - Animals

KW - Autoradiography

KW - Biomarkers, Tumor

KW - Brain Neoplasms

KW - Cells, Cultured

KW - Copper Radioisotopes

KW - Female

KW - Glioblastoma

KW - Humans

KW - Male

KW - Mice

KW - Middle Aged

KW - Positron-Emission Tomography

KW - RNA, Messenger

KW - Radiopharmaceuticals

KW - Receptors

KW - Survival Analysis

KW - Xenograft Model Antitumor Assays

KW - Urokinase Plasminogen Activator

U2 - 10.2967/jnumed.115.161703

DO - 10.2967/jnumed.115.161703

M3 - Journal article

C2 - 26429955

SN - 0161-5505

VL - 57

SP - 272

EP - 278

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

IS - 2

ER -

Urokinase-Type Plasminogen Activator Receptor as a Potential PET Biomarker in Glioblastoma

Abstract

Keywords

UN SDGs

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