It takes two to tango: Combinations of conventional cytotoxics with compounds targeting the vascular endothelial growth factor-vascular endothelial growth factor receptor pathway in patients with solid malignancies

Through advances in molecular biology, insight into the mechanisms driving malignancies has improved immensely and as a result, various factors playing an essential role in the biology of numerous tumor types have been revealed. By using compounds that specifically block the function of a single factor being crucial for tumor pathogenesis, it was hoped to exert antitumor activity while avoiding toxicities characteristic for conventional chemotherapy. One of the processes of crucial importance in the development of cancer, and consequently an attractive target, is angiogenesis. In recent years, several key factors for angiogenesis have been identified, including ligands, receptors, and transduction signaling factors. Of these, the vascular endothelial growth factor (VEGF) pathway has been found to be activated in numerous tumor types and considered one of the main drivers of angiogenesis. Roughly, VEGF-mediated angiogenesis can be inhibited by two approaches: either by monoclonal antibodies directed towards VEGF or its corresponding receptors, or by kinase inhibitors targeting the signal transduction of the VEGF receptors. As monotherapy, several kinase inhibitors exert antitumor activity in tumor types such as renal cell carcinoma. However, in most tumor types, the antitumor activity of compounds targeting the VEGF pathway is limited. In recent years, evidence is mounting that the paradigm of one single factor that drives malignant behavior applies rarely and is an oversimplification for most tumors in which there are multiple driving pathways. Consequently, multitargeting rather than single-targeting approaches are required. One of the means is by combining targeted agents with conventional cytotoxics. As the VEGF pathway also affects the sensitivity of tumor cells to chemotherapeutics, combinations of compounds targeting this pathway and conventional cytotoxics have been explored. This review addresses such combinations.

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