Abstract
Simple SummaryAmong multiple other functional roles of tissue factor (TF) and other coagulation proteins in the development and targeting of malignant disease, some scientific groups are attempting to modify TF and target the molecule or truncated forms of the molecule to tumor vasculature to selectively induce local blood vessel thromboembolic occlusion resulting in tumor infarction. This review briefly describes the characteristics and development of some of these proteins and structures, including tTF-NGR, which as the first drug candidate from this class has entered clinical trials in cancer patients.Besides its central functional role in coagulation, TF has been described as being operational in the development of malignancies and is currently being studied as a possible therapeutic tool against cancer. One of the avenues being explored is retargeting TF or its truncated extracellular part (tTF) to the tumor vasculature to induce tumor vessel occlusion and tumor infarction. To this end, multiple structures on tumor vascular wall cells have been studied at which tTF has been aimed via antibodies, derivatives, or as bifunctional fusion protein through targeting peptides. Among these targets were vascular adhesion molecules, oncofetal variants of fibronectin, prostate-specific membrane antigens, vascular endothelial growth factor receptors and co-receptors, integrins, fibroblast activation proteins, NG2 proteoglycan, microthrombus-associated fibrin-fibronectin, and aminopeptidase N. Targeting was also attempted toward cellular membranes within an acidic milieu or toward necrotic tumor areas. tTF-NGR, targeting tTF primarily at aminopeptidase N on angiogenic endothelial cells, was the first drug candidate from this emerging class of coaguligands translated to clinical studies in cancer patients. Upon completion of a phase I study, tTF-NGR entered randomized studies in oncology to test the therapeutic impact of this novel therapeutic modality.
Highlights
Tissue factor (TF) is a 47-kDa membrane-bound cell surface receptor which functions as primum movens of the extrinsic pathway in coagulation [1,2]
As thromboembolism is a cause of death in cancer patients receiving chemotherapy [6], standards of anticoagulation in these patients are fine-tuned by numerous clinical studies
We have repeatedly found single doses of 0.5 mg/kg body weight to be ineffective for tumor growth inhibition and 0.75 mg/kg as a dose with marginal activity
Summary
Tissue factor (TF) is a 47-kDa membrane-bound cell surface receptor which functions as primum movens of the extrinsic pathway in coagulation [1,2]. In an attempt opposite to what has been described so far, several groups including our laboratory have tried to target TF or procoagulatory parts of the molecule at the tumor vasculature to selectively induce tumor vessel occlusion with resulting tumor infarction, tumor shrinkage, or inhibition of further tumor growth and spread. This field was kicked off by the ground-breaking hypothesis of J.
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