Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions

Naveen S Vasudev,Andrew R Reynolds

doi:10.1007/s10456-014-9420-y

Abstract

Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies.

Highlights

The concept of ‘anti-angiogenic therapy’ arose from the seminal observations of Judah Folkman and colleagues
We present a succinct review of the progress with vascular endothelial growth factor (VEGF)-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages, interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness
We review the progress of VEGF-targeted therapies in the clinic, discuss the current questions and controversies that exist in the field and propose routes to more effective and personalised anti-angiogenic therapy

Summary

Introduction

The concept of ‘anti-angiogenic therapy’ arose from the seminal observations of Judah Folkman and colleagues. In patients with colorectal liver metastases treated with bevacizumab and chemotherapy, changes in tumour morphology on CT were shown to associate more significantly with overall survival than the use of RECIST criteria [124] These studies suggest a promising role for imaging as a predictive marker in certain settings, many challenges remain. Despite this, tumours have been shown to progress through treatment with these agents in many indications, including metastatic breast cancer [44,45,46,47], glioblastoma [75], hepatocellular carcinoma [145, 146] and mRCC [147] This is in contrast to preclinical studies demonstrating a role for alternative growth factor signalling pathways and questions the relevance of alternative proangiogenic growth factors in mediating resistance to antiangiogenic therapy in patients. Analysis of human cancers reveals vessel co-option in glioblastoma [182, 183], adenocarcinoma of the lung [184, 185] cutaneous melanoma [186], lung metastases of breast and renal cancer [187,188,189], liver metastases of colorectal and breast

E Alternative vascularisation mechanisms Intussusceptive microvascular growth

Findings

Conclusions