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

Abstract

One of the largest challenges to the implementation of precision oncology is identifying and validating selective tumor-driving targets to enhance the therapeutic efficacy while limiting off-target toxicity. In this context, the urokinase-type plasminogen activator receptor (uPAR) has progressively emerged as a promising therapeutic target in the management of aggressive malignancies. By focalizing the plasminogen activation cascade and subsequent extracellular proteolysis on the cell surface of migrating cells, uPAR endows malignant cells with a high proteolytic and migratory potential to dissolve the restraining extracellular matrix (ECM) barriers and metastasize to distant sites. uPAR is also assumed to choreograph multiple other neoplastic stages via a complex molecular interplay with distinct cancer-associated signaling pathways. Accordingly, high uPAR expression is observed in virtually all human cancers and is frequently associated with poor patient prognosis and survival. The promising therapeutic potential unveiled by the pleiotropic nature of this receptor has prompted the development of distinct targeted intervention strategies. The present review will focus on recently emerged cytotoxic approaches emphasizing the novel technologies and related limits hindering their application in the clinical setting. Finally, future research directions and emerging opportunities in the field of uPAR targeting are also discussed.

Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View

“…However, despite the advances in the molecular design and generation of uPAR-derived peptides or novel interactors, no uPAR-targeting therapeutics have currently progressed to clinical trials ( Metrangolo et al, 2021 ). Most studies are at preclinical stages and further analyses of the biodistribution, toxicity profile, pharmacokinetics of the novel agents in vivo are needed to assess their potential benefits in a clinical setting.…”

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

“…FAP features a unique dual dipeptidyl peptidase and endopeptidase activity, which distinguishes it from DPP4 and other members of the S9 family [99,100]. The first inhibitors Glu-boroPro (PT-630) and Val-boroPro (PT-100, talabostat ® ) target not only FAP, but also DPP4 and/or DPP8/9 (reviewed in [10,101]). They had no effect on tumour cell growth in vitro or in immunodeficient mice, suggesting that these inhibitors targeted the immune system [57,102].…”

“…and tumour associated EVs that are promising not only as biomarkers, but also as therapeutic targets for cancer therapy. The list of ectoproteases as potential targets for cancer therapy is further expanding, as has already been seen with other ADAMs (including ADAM8, ADAM10, ADAM28), MT1-MMP/MMP14, the complex urokinase plasminogen (uPA)/uPAR, and neutral endopeptidase N/CD10 overexpressed in solid and haematological tumours [19,101,290,291]. Biomarker-guided trial design is recognized as pivotal in advancing the field of personalized medicine [292,293].…”

Clinical Efficacy of Xueshuantong plus Urokinase in the Treatment of Sudden Deafness

“…Urokinase is one of the commonly used drugs for the clinical treatment of patients with sudden deafness [ 9 ]. As a thrombolytic drug, it can act well on the endogenous fibrinolytic system and catalyze the cleavage of plasminogen into plasmin.…”