PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives

Abstract

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-DOTA-AE105 was found in both primary tumors and lymph node metastases. The results are encouraging and support large-scale clinical trials to determine the utility of uPAR PET in the management of patients with PC with the goal of improving outcome.

ImmunoPET: Concept, Design, and Applications

“…Urokinase plasminogen activator (uPA) receptor (uPAR) is one of the validated targets. AE105, a high-affinity peptide antagonist against uPAR, has been radiolabeled and investigated extensively in preclinical studies . Inspired by the preclinical success, 64 Cu-DOTA-AE105 and 68 Ga-NOTA-AE105 have been successfully translated into the clinic for PET imaging of uPAR in patients with solid tumors. , Using an IgG1 mAb (ATN-291) specifically targeting human uPA, Yang and co-workers developed a radiotracer 89 Zr-Df-ATN-291 .…”

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

“…As alluded to in the previous sections, the ubiquitous uPAR expression at the tumor–stromal interface of several invading cancer lesions makes it an appealing molecular imaging target for the clinical assessment of tumor invasion and metastatic dissemination. Accordingly, a plethora of uPAR-targeting PET-probes mostly based on the high-affinity 9-mer antagonist peptide AE105 have been synthesized and tested preclinically in diverse human xenograft mouse models and, recently, also in two clinical uPAR PET studies in humans, including prostate, breast, and bladder cancer patients, with promising results [ 17 , 22 , 23 , 24 , 25 , 28 , 160 ]. A thorough overview of the versatile applications of AE105 for non-invasive imaging of cancer is provided by the following review [ 26 ].…”

“…Distinct uPAR-binding agents, including anti-uPAR monoclonal antibodies, uPA-derived peptides, and the amino-terminal fragment of uPA (ATF, which contains the receptor-binding domain) have been widely exploited as uPAR-targeting vehicles. Similar principles have been successfully applied for the development of uPAR-directed imaging probes to detect receptor-positive malignant lesions, monitoring intratumoral drug delivery and antitumor effects of uPAR-targeted interventions, both in preclinical and clinical settings [ 17 , 22 , 23 , 24 , 25 , 26 ]. The design and implementation of theranostic approaches combining uPAR-targeted therapeutic and non-invasive imaging modalities, such as positron emission tomography (PET), magnetic resonance (MRI), or near-infrared (NIR) fluorescence imaging, are currently underway and hold clinical potential for significantly improving patient management and disease outcomes, as evidenced by the encouraging results achieved for prostate cancer in recent years [ 27 , 28 ].…”

Application Research of Small Molecule Peptide Screening Based on Cancer Cells

“…In clinical application, 19 peptides are commonly used through intravenous injection, because its molecular weight is very low and the drug safety is high. If multiple targets are pulled by 19 peptides, the drug can be delivered directly to the tumor cells [6], and then improve the efficiency of medicine [7].…”