Antiangiogenesis and vascular disrupting agents in cancer: circumventing resistance and augmenting their therapeutic utility

Angiogenesis is a process essential for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown only moderately improved results and is beset with practical limitations, despite theoretical therapeutic advantages. Inevitably resistance develops, through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions, with more invasive phenotypes. Antiangiogenic-targeted therapies may find improved efficacy in combination therapies; with others in this class, that directly or indirectly target separate pathways or different components of the same pathway, or with a separate class of tumor vasculature-disrupting agents. This review discusses the challenges and strategies for optimization of combination therapies including metronomic administration of drugs and the need for suitable prognostic and surrogate response biomarkers.