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

Vasudev NS, Reynolds AR - Angiogenesis (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK.

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.

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Related in: MedlinePlus

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
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Fig1: 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

Mentions: The concept of ‘anti-angiogenic therapy’ arose from the seminal observations of Judah Folkman and colleagues. Pre-clinical studies showed that tumours induce the sprouting of new vessels from the surrounding vasculature (sprouting angiogenesis) and that this process is vital for the growth of tumours beyond 2–3 mm in size (Fig. 1). It was therefore proposed that inhibition of sprouting angiogenesis could suppress tumour growth in humans [1]. Further studies established that (a) vascular endothelial growth factor-A (VEGF) is a key driver of sprouting angiogenesis, (b) VEGF is overexpressed in most solid cancers, and (c) inhibition of VEGF can suppress tumour growth in animal models [2–4]. Based on these observations, numerous therapies have been developed that target angiogenesis by blocking the VEGF signalling pathway (Fig. 2). The biology of VEGF signalling, angiogenesis and the principles upon which anti-angiogenic therapy is based have been extensively reviewed [2, 5–8]. Here we review the progress of VEGF-targeted therapies in the clinic (see also Table 1), discuss the current questions and controversies that exist in the field and propose routes to more effective and personalised anti-angiogenic therapy.Fig. 1


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

Vasudev NS, Reynolds AR - Angiogenesis (2014)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4061466&req=5

Fig1: 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
Mentions: The concept of ‘anti-angiogenic therapy’ arose from the seminal observations of Judah Folkman and colleagues. Pre-clinical studies showed that tumours induce the sprouting of new vessels from the surrounding vasculature (sprouting angiogenesis) and that this process is vital for the growth of tumours beyond 2–3 mm in size (Fig. 1). It was therefore proposed that inhibition of sprouting angiogenesis could suppress tumour growth in humans [1]. Further studies established that (a) vascular endothelial growth factor-A (VEGF) is a key driver of sprouting angiogenesis, (b) VEGF is overexpressed in most solid cancers, and (c) inhibition of VEGF can suppress tumour growth in animal models [2–4]. Based on these observations, numerous therapies have been developed that target angiogenesis by blocking the VEGF signalling pathway (Fig. 2). The biology of VEGF signalling, angiogenesis and the principles upon which anti-angiogenic therapy is based have been extensively reviewed [2, 5–8]. Here we review the progress of VEGF-targeted therapies in the clinic (see also Table 1), discuss the current questions and controversies that exist in the field and propose routes to more effective and personalised anti-angiogenic therapy.Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Tumour Biology Team, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK.

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.

Show MeSH
Related in: MedlinePlus