New antiangiogenic strategies beyond inhibition of vascular endothelial growth factor with special focus on axon guidance molecules.

Since the approval of the first antiangiogenic agent bevacizumab, a neutralizing antibody against the vascular endothelial growth factor (VEGF), antiangiogenic therapies augmented the standard armamentarium of anticancer therapies and proved their clinical efficacy. Nevertheless, antiangiogenic strategies could not fulfill the expected hopes. In clinical routine, therapy responses to antiangiogenic therapies were mostly transient and most of the patients developed evasive resistance mechanisms during therapy. Further, no predictive biomarker for therapy response could be developed, hampering the clinical development of these agents and triggering skepticism. In the past years, knowledge on the biology of angiogenesis increased and the role of tumor hypoxia was better characterized and identified as the driver for angiogenic regulation mechanisms. Besides VEGF, new angiogenic and antiangiogenic factors were characterized and the process of endothelial cell migration, proliferation and vessel formation was better elucidated. Thus, a strong connection to neural development and axon guidance molecules like netrins, Slit proteins, semaphorins, ephrins and their cognate receptors UNC5, Robo1-4, neuropilin and EphB was identified. The aim of this review is to present the importance of these axon guidance molecules with special focus on Robo4 and semaphorins in tumor angiogenesis and to highlight their value as potential targets for new antiangiogenic therapies.