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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

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)
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Fig3: 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)

Mentions: Insight into this tumour-stromal relationship in the setting of intrinsic resistance can be gained from studies in mRCC patients, which examined both change in tumour blood flow and change in lesion size in clinically detectable tumours upon treatment with single agent anti-angiogenic therapy [121–123]. In some cases, a strong vascular response may be observed, which is accompanied by significant tumour shrinkage (Fig. 3a) [121–123]. Tumours undergoing this type of response probably fulfil two important conditions: (a) the growth and survival of the vasculature is very sensitive to the agent, and (b) tumour cell survival is highly dependent on the vascular supply. In the second instance, despite a strong vascular response, tumour growth is only stabilised (Fig. 3b) [121–123]. In this scenario, tumour cells may be adapted to survive, despite a reduction in vascular supply. In the third instance, the targeted agent results in minimal or insignificant suppression of the tumour vascular supply, resulting in stabilisation of disease or tumour progression (Fig. 3c) [121–123]. In this scenario, the growth and survival of the vasculature is apparently poorly sensitive to the agent.Fig. 3


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

Vasudev NS, Reynolds AR - Angiogenesis (2014)

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)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: 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)
Mentions: Insight into this tumour-stromal relationship in the setting of intrinsic resistance can be gained from studies in mRCC patients, which examined both change in tumour blood flow and change in lesion size in clinically detectable tumours upon treatment with single agent anti-angiogenic therapy [121–123]. In some cases, a strong vascular response may be observed, which is accompanied by significant tumour shrinkage (Fig. 3a) [121–123]. Tumours undergoing this type of response probably fulfil two important conditions: (a) the growth and survival of the vasculature is very sensitive to the agent, and (b) tumour cell survival is highly dependent on the vascular supply. In the second instance, despite a strong vascular response, tumour growth is only stabilised (Fig. 3b) [121–123]. In this scenario, tumour cells may be adapted to survive, despite a reduction in vascular supply. In the third instance, the targeted agent results in minimal or insignificant suppression of the tumour vascular supply, resulting in stabilisation of disease or tumour progression (Fig. 3c) [121–123]. In this scenario, the growth and survival of the vasculature is apparently poorly sensitive to the agent.Fig. 3

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