Abstract
Simple SummaryDiscovered more than three decades ago, the urokinase-type plasminogen activator receptor (uPAR) has now firmly established itself as a versatile molecular target holding promise for the treatment of aggressive malignancies. The copious abundance of uPAR in virtually all human cancerous tissues versus their healthy counterparts has fostered a gradual shift in the therapeutic landscape targeting this receptor from function inhibition to cytotoxic approaches to selectively eradicate the uPAR-expressing cells by delivering a targeted cytotoxic insult. Multiple avenues are being explored in a preclinical setting, including the more innovative immune- or stroma targeting therapies. This review discusses the current state of these strategies, their potentialities, and challenges, along with future directions in the field of uPAR targeting.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.
Highlights
The design and implementation of theranostic approaches combining urokinase-type plasminogen activator receptor (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]
Compared to the parental monospecific cytotoxins, DTATEGF exhibited more than 100- to 1000-fold more potent antitumor efficacy both in vitro (IC50 = 0.001 nM) and in vivo when administered intracranially by convection-enhanced delivery (CED) via an osmotic minipump, providing a significant survival benefit relative to the controls [187]
These encouraging preclinical results underscore the potential of bispecific agents, such as DTATEGF and DTAT13, whose enhanced targeting specificity may improve treatment of heterogeneous tumors while simultaneously reducing off-target toxicity, thereby warranting their further clinical investigation [181]
Summary
Most drug development is oriented toward the design of cancer-cell-targeted cytotoxic interventions [1]. 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]. Novel opportunities and future directions of uPAR therapeutic targeting will be presented
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