The Oral Serine Protease Inhibitor WX-671 – First Experience in Patients with Advanced Head and Neck Carcinoma

Tumour invasion and metastasis depend on the capacity of tumour cells to coordinate various biological processes such as detachment of cells from their original localisation, cancer cell migration, invasion of cancer cells into surrounding tissue, access to blood and lymphatic vessels and adhesion to and invasion through the endothelium, allowing colonisation at distant sites of the organism. This complex scenario requires the concerted and regulated expression of extracellular proteolytic systems, integrins and adhesion proteins. Degradation of proteins in basement membranes and extracellular matrix is the prerequisite for the invasion of cells and the formation of metastases. This is mediated by various extracellular proteolytic enzymes including serine proteinases, metalloproteinases and cysteine proteinases [1]. There is abundant experimental evidence that the plasminogen activator system plays an essential role in these processes [1,2,3,4,5,6,7,8]. It consists of two serine proteinases, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), the cell surface uPA receptor (uPAR) and the plasminogen activator inhibitors 1 and 2 (PAI-1, PAI-2). uPA is agreed to be the enzyme with the major influence on cancer-related processes, whereas the primary role of tPA is the generation of plasmin for fibrinolysis of blood vessels [9]. Besides its proteolytic activity, uPA in concert with uPAR also mediates mitogenic, adhesive and migratory processes [10]. Clinical studies have demonstrated the relevance of uPA, uPAR and PAI-1 in malignant tumours such as breast, ovary, cervical, upper urinary, gastrointestinal, lung, prostate and other cancers. Elevated levels of these factors correlate with increased malignancy and poor patient outcome [1, 7, 11, 12]. For head and neck squamous cell carcinoma (HNSCC) the role of the uPA system has been extensively investigated [13,14,15,16,17]. In tumour lysates, it has been demonstrated that both uPA and PAI-1 may play a specific role in the process of invasion and metastasis and might also be of prognostic value in this carcinoma [18, 19]. Recently, Wilex developed a serine protease inhibitor of the uPA system, the intravenous drug WX-UK1, and its new orally administered pro-drug WX-671 to treat cancer. Once WX-671 is absorbed, the hydroxyamidino function is reductively converted to the amidino function, thereby generating pharmacologically active WX-UK1. In rat, dog and monkey, WX-671 is effectively absorbed, although with varying rates between species, and readily metabolised to WX-UK1. In rat models, WX-671 has been shown to be efficacious at inhibiting tumour growth and spread. For clinical testing in man, hard gelatine capsules are available that contain WX-671 hydrogen sulphate equivalent to 50 mg and 200 mg WX-671 (free base). The aim of this study was to evaluate the pharmacokinetics of both the oral pro-drug WX-671 and the metabolite WX-UK1 in human tissue and plasma of patients with HNSCC. In addition, the safety and tolerability as well as the effects on the uPA system of WX-671 were assessed.