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

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.

Fig. 1

The role of sprouting angiogenesis in tumour growth. Early observations on the growth of tumours supported the following model for how tumours obtain a vascular supply. a When a tumour mass is small, it can obtain oxygen and nutrients from existing local blood vessels. b As the tumour grows beyond the capacity of local blood vessels, soluble pro-angiogenic factors are released which promote the sprouting of new vessels from local existing blood vessels (sprouting angiogenesis). c These vessels provide a blood supply for the tumour and this is required in order for the tumour to grow beyond 2–3 mm in size

Fig. 2

VEGF-targeted agents. The VEGF signalling system in mammals is complex and consists of five related ligands, VEGF-A, VEGF-B, VEGF-C, VEGF-D and PLGF that bind with different specificities to three receptor tyrosine kinases, VEGFR1, VEGFR2 and VEGFR3. The biology of these interactions has been extensively reviewed [231, 233]. Shown is a highly simplified diagram designed to illustrate the three major classes of agent that target this signalling system: (a) ligand binding agents that block the binding of VEGF ligands to receptors (e.g. bevacizumab which binds to VEGF-A alone and aflibercept which binds to VEGF-A, VEGF-B and PLGF), (b) antibodies that block signalling through VEGF receptors (e.g. ramucirumab which binds to VEGFR2) and (c) tyrosine kinase inhibitors which block the kinase activity of VEGFR1, VEGFR2 and VEGFR3 (e.g. sorafenib, sunitinib, pazopanib). Note that these tyrosine kinase inhibitors can also can inhibit the kinase activity of some other receptor tyrosine kinases, including platelet derived growth factor receptors (PDGFRs), c-Kit and fms-related tyrosine kinase (FLT3) [233]

Fig. 3

Response and resistance to anti-angiogenic therapy. Tumours may respond initially to anti-angiogenic therapy in different ways. a Therapy results in a strong vascular response (a significant reduction in the amount of perfused tumour vessels) and significant tumour shrinkage. b Therapy results in a strong vascular response, but only stabilisation of disease is achieved. c Therapy results in a poor vascular response (minimal reduction in the amount of perfused tumour vessels) and tumour stabilises or progresses. d, e After a period of response, acquired resistance can occur. This may be due to the activation of alternative angiogenic pathways (d) or because tumour cells adapt to the lack of a vascular supply via various potential mechanisms (e)

Fig. 4

Potential mechanisms involved in resistance to VEGF-targeted therapy. a Tumours present with a mixture of therapy-sensitive and therapy-insensitive vessels. The top vessel is destroyed by the therapy (depicted in grey), whilst the bottom one remains (depicted in red). b Alternative signalling pathways can regulate the sensitivity of vessels to therapy. In the panel, the tumour cells (in blue) have up-regulated an alternative pro-angiogenic growth factor in order to drive blood vessel growth and survival. c Stromal cells, such as immature myeloid cells (black) or fibroblasts (green) infiltrate the tumour and mediate resistance either by releasing pro-angiogenic growth factors or by physically incorporating into vessels. d Tumour cells can survive conditions of stress. Some tumour cells (depicted in blue) have survived the loss of a vascular supply, because they are adapted to survive conditions of hypoxia or nutrient shortage. e Tumours may use alternative mechanisms of vascularisation besides sprouting angiogenesis. In intussusceptive microvascular growth new vessels are generated by the fission of existing vessels. Glomeruloid angiogenesis is characterised by tight nests of vessels that resmemble the renal glomerulus. In vasculogenic mimicry, tumour cells directly form vascular channels (blue cells) that are perfused via connection to the host vasculature (red cells). In looping angiogenesis, contractile myofibroblasts (green) pull host vessels out of the normal surrounding tissue (pink region). In vessel co-option tumour cells engulf host vessels in the normal surrounding tissue (pink region) as the tumour invades. f Increased tumour aggressiveness i.e. therapy causes tumour to become more invasive and/or accelerates the growth of metastases