Targeting the VEGF pathway
VEGF (vascular endothelial growth factor) is responsible for many effects on tumour vasculature, including endothelial cell proliferation, migration, invasion, vascular permeability and vasodilation and even the chemotaxis of bone marrow precursors. Several approaches have been developed to block the actions of VEGF: blocking circulating VEGF, blocking its receptor (VEGFR) or inhibition of signalling mediated by VEGF.
The effectiveness of anti-angiogenic drugs has been demonstrated in monotherapy for renal cancer, hepatocellular carcinoma and medullary carcinoma of the thyroid. Benefits have also been observed in combination with conventional chemotherapy, in particular in non-small cell lung cancer, metastatic colorectal cancer, ovarian cancer and possibly breast cancer.
This publication also covers the toxicities associated with anti-angiogenic drugs, which can be divided into two main groups:
- “class” effects: hypertension, proteinuria, cardiomyopathy, arterial thrombosis, haemorrhage, thrombotic microangiopathy, gastrointestinal perforations, delayed healing etc.;
- effects specific to each drug: hypothyroidism, myelosuppression, mucositis, hand-foot syndromes etc.
Tumour characteristics (for example localisation or histology) and patient characteristics can increase the risk of toxicity and therefore must be taken into account when prescribing anti-angiogenic drugs.
A number of predictive biomarkers of response to anti-angiogenic drugs have been evaluated: tumour biomarkers (VEGF expression, tumour perfusion), patient-related clinical biomarkers (change in blood pressure), circulating blood biomarkers (circulating VEGF level, cytokines, circulating endothelial cells) and biomarkers based on imaging. The latter now seem to be the most reliable, but several investigations are underway in this field.