PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives
PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives
Dorthe Skovgaard 0 1 2
Morten Persson 0 1 2
Andreas Kjaer 0 1 2
0 Curasight , Copenhagen , Denmark
1 Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, National University Hospital , Blegdamsvej 9, 2100 Copenhagen , Denmark
2 & Andreas Kjaer
Overexpression of urokinase-type plasminogen activator receptors (uPAR) represents an important biomarker for aggressiveness in most common malignant diseases, including prostate cancer (PC). Accordingly, uPAR expression either assessed directly in malignant PC tissue or assessed directly in plasma (intact/cleaved forms)-provides independent additional clinical information to that contributed by PSA, Gleason score, and other relevant pathological and clinical parameters. In this respect, non-invasive molecular imaging by positron emission tomography (PET) offers a very attractive technology platform, which can provide the required quantitative information on the uPAR expression profile, without the need for invasive procedures and the risk of missing the target due to tumor heterogeneity. These observations support non-invasive PET imaging of uPAR in PC as a clinically relevant diagnostic and prognostic imaging method. In this review, we will focus on the recent development of uPAR PET and the relevance within prostate cancer imaging. Novel antibody and small-molecule radiotracers-targeting uPAR, including a series of uPAR-targeting PET ligands, based on the high affinity peptide ligand AE105, have been synthesized and tested in vitro and in vivo in preclinical murine xenograft models and, recently, in a first-ever clinical uPAR PET study in cancer patients, including patients with PC. In this phase I study, a high and specific uptake of the tracer 64Cu-DOTAAE105 was found in both primary tumors and lymph node metastases. The results are encouraging and support largescale clinical trials to determine the utility of uPAR PET in the management of patients with PC with the goal of improving outcome.
uPAR; PET imaging; Theranostics; Prostate cancer; Radionuclide; Molecular imaging
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D. Skovgaard, M. Persson, and A. Kjaer authors contributed equally
to this work.
Introduction
Prostate cancer (PC) is the most commonly diagnosed
cancer amongst men in western countries [
1
]. The prognosis
of PC is highly variable, with some PCs remaining latent
disease not causing any clinical symptoms or morbidity,
whereas other PCs are aggressive and associated with fast
progression and high mortality [
1, 2
]. Due to limitations of
the currently available diagnostic and prognostic tools,
over-diagnosis and unnecessary treatment of indolent
disease are a major issue, and novel diagnostic and/or
prognostic biomarkers for PC are urgently needed [
1, 3
].
New sophisticated molecular imaging modalities with
multiparametric magnetic resonance imaging (mpMRI)
and positron emission tomography (PET) using
18F-fluorodeoxy-glucose (FDG), radiolabeled choline, and alternative
radioligands, such as gastrin-releasing peptide receptor
(GRPR)-targeting ligand and prostate-specific membrane
antigen (PSMA)-targeting ligand, are currently
investigated for all aspects of PC, including diagnosis and
localization, staging, active surveillance, prognosis, and
monitoring recurrence [
1
].
In this review, we will focus on PET imaging of a new
promising molecular target; urokinase-type plasminogen
activator receptor (uPAR) in PC as a clinically relevant
diagnostic and prognostic imaging biomarker with the
possibility of distinguishing indolent tumors from the
invasive phenotype. The majority of references for this
review were found by searching PubMed for ‘‘uPAR’’,
‘‘urokinase-type plasminogen activator receptor’’,
‘‘prostate cancer’’, and ‘PET’ or ‘positron emission tomography’.
Additional references were also incorporated on the basis
of the author’s experience in basic research within uPAR or
related fields as well as by cross-referencing.
uPAR and the aggressive phenotype
The urokinase plasminogen activator (PA) system plays a
key role in the pericellular proteolytic activity which is
required for tissue remodeling during normal physiological
conditions, such as wound healing and initiation of
angiogenesis, but also in pathophysiologically processes,
such as cancer invasion [
2–7
] (Fig. 1). The PA system
consists of the serine protease urokinase-type plasminogen
(uPA), its glycosylphosphatidylinositol (GPI)-anchored
cell membrane receptor (uPAR), and two specific inhibitors
PAI-1 and PAI-2. uPA binds with high affinity to uPAR
and, consequently, converts plasminogen to active plasmin,
which activates several proteases related to the degradation
of extracellular matrix proteins and basal membranes,
thereby facilitating cancer cell invasion and metastasis [8].
It has become increasin (...truncated)