Vandetanib (ZD6474), a novel multitargeted kinase inhibitor, in cancer therapy

Abstract

In clinical trials thus far, single-targeted kinase inhibitors have shown only limited success in demonstrating survival benefits in cancer. This has led to the development of multitargeted kinase inhibitors capable of disrupting various mitogenic pathways in both cancer cells and associated vasculature. Vandetanib is a novel multitargeted kinase inhibitor exhibiting potent activity against vascular endothelial growth factor receptor-2 (VEGFR-2; kinase insert domain-containing receptor [KDR]) and, to a lesser extent, epidermal growth factor receptor (EGFR) and RET kinase. Vascular endothelial growth factor (VEGF) and VEGFR-2 play a pivotal role in regulating angiogenesis and vascular permeability in cancers. In addition to its antiangiogenic effects, vandetanib acts against EGFR, which is overexpressed or mutated in several solid tumors. Furthermore, vandetanib exerts activity against oncogenic RET kinase, the overexpression of which is common in medullary and papillary thyroid carcinomas. Therefore, the multitargeted kinase inhibitor vandetanib represents a new approach, targeting both tumor cells and tumor-associated endothelial cells. Preclinical studies of vandetanib have demonstrated antitumor efficacy against multiple human cancer xenografts in subcutaneous, orthotopic and metastatic models. Phase I clinical trials have demonstrated that vandetanib is well tolerated. Common adverse events included rash, diarrhea and asymptomatic QTc prolongation. Phase II clinical studies in patients with non-small-cell lung cancer have shown promising results, employing vandetanib as both monotherapy and in combination with docetaxel. Phase II studies in other cancers have likewise been initiated. This review summarizes preclinical and clinical studies of vandetanib for the treatment of cancers.