Personalising and targeting antiangiogenic resistance: a complex and multifactorial approach

Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical and clinical data suggest that tumours can show dual, different adaptive responses against antiangiogenic agents: one successful adaptation is vascular normalisation, whereas the second adaptation is elicited through vascular trimming and increased hypoxia. These phenomena depend on the type of tumour and the type of agent. The classical approach for investigating acquired resistance against antiangiogenic agents is to identify compensatory signalling pathways emerging in response to VEGF blockade, which has led to the development of highly effective drugs; however, ultimately these drugs fail. Here we review how the dual stromal adaptive patterns determine the mechanisms of escape that go beyond the reprogramming of signal transduction pathways, which obliges us to investigate the tumour as an ecosystem and to develop uni- and multicompartmental models that explain drug resistance involving metabolic and immune reprogramming. We also propose a method for facilitating personalised therapeutic decisions, which uses 18F-fluoromisonidazole-positron emission tomography to monitor the dual stromal response in tumours of individual patients.