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Approaches to VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour) inhibition

Direct and continuous VEGF inhibition as an antitumour strategy

Emerging preclinical evidence continues to shed light on important questions in angiogenesis(The growth of new blood vessels from pre-existing vessels) research, including how to optimally target critical angiogenic growth factors. Among these factors, VEGF has been identified as the most predominant. In the quest to inhibit this key pathway, two primary strategies have arisen – inhibition of either the VEGF ligand(A substance that forms a complex with a biomolecule to serve a biological purpose) or the VEGF receptor(Proteins located on the cell surface. When a specific molecule called a ligand binds to a receptor, signalling pathways are activated). This section takes a detailed look at these two related - but distinct - antitumour approaches.

Strategies for inhibiting the VEGF pathway

While VEGF is the predominant mediator of angiogenesis, there are different strategies for inhibiting its pathway. The two primary strategies include inhibiting either the VEGF ligand (e.g. ligand antibodies or soluble receptors) or the VEGF receptor (e.g. TKIs or receptor antibodies).1 Anti-VEGF strategies that specifically target the ligand, such as VEGF antibodies, specifically inhibit pathways mediated by VEGF and therefore may inhibit angiogenesis without disrupting other ‘off target’ pathways.2–4 Anti-VEGF strategies that target the receptor, such as TKIs, have a wider range of inhibitory effects and may disrupt other secondary pathways that are also mediated through receptor kinases – a factor associated with unwanted non-VEGF mediated side effects.2,3,5–7

In addition, directly targeting VEGF has been shown to result in important antivascular effects that may be sustainable. In both preclinical and clinical models, an anti-VEGF antibody significantly reduced microvascular density(A widely applied morphologic measure of vascularisation), intratumoural pressure and neovascularisation(The formation of functional microvascular networks with red blood cell perfusion).8–11 These effects have been observed to occur rapidly (in some cases, after a single infusion). It is also important to note that the relatively long half-life of monoclonal  antibodies potentially allows for a maintained anti-VEGF effect.2,8

Proposed MoA of anti-VEGF agents

Based on preclinical models and clinical observations, it has been proposed that anti-VEGF agents exert continuous anti-angiogenic effects throughout tumour(An abnormal growth of cells, forming a mass of tissue) development. One of the most rapid of these proposed effects is regression(A characteristic of diseases to show lighter symptoms without completely disappearing. At a later point, symptoms may return ) of existing tumour vessels. Direct and rapid changes observed with anti-VEGF agents include a significant reduction in microvascular density.8,11–13 While some aberrant tumour microvasculature may be regressed,11 the permeability of surviving mature vasculature may be reduced.14–18 In addition to these more rapid effects, anti-VEGF agents may also result in ongoing inhibition of both new and recurrent tumour vessel growth.9,10,13 It has been proposed that these effects inhibit tumour growth and metastasis(The spread of a disease from one organ or part to another non-adjacent organ or part).19–22

Versatility to address changing tumour biology

The current understanding of tumour biology, based primarily on preclinical observations, suggests that antitumour strategies must be made versatile over time in order to remain effective.23 In particular, while multiple angiogenic factors may be activated over the course of a tumour life cycle, continuously expressed VEGF is the only one known to be critical throughout.25 Therefore, the strategy of maintaining direct inhibition of VEGF – supplemented by selective targeting of secondary pathways as they emerge – continues to be explored in both the laboratory and the clinic.26,27

As observed in preclinical models, the ability to maintain precise VEGF inhibition as part of an overall antitumour strategy may be a function of the specificity of direct VEGF inhibitors. This specificity may facilitate combination with approaches that target other mechanisms of tumour proliferation(The reproduction of cells by multiplication of parts).2,6

Indeed, the anti-angiogenic effects of precise VEGF inhibition have been observed in a wide range of preclinical settings. In addition to antitumour activity demonstrated in single-agent experiments, precise VEGF inhibition has been shown to be active in combination with a range of modalities that target other mechanisms of tumour proliferation.24 This ability to apply precise and continuous VEGF inhibition, either alone or with other modalities, may add versatility to an overall antitumour approach.23 Further preclinical investigation is ongoing to further evaluate the versatility of precise VEGF inhibition.

Continuous VEGF inhibition: a promising treatment strategy

A stable target that is continually expressed

One important question in angiogenesis research is: for how long should inhibition of various pro-angiogenic factors be maintained? As preclinical evidence now suggests, because VEGF is thought to be genetically stable and continuously expressed, it can potentially be targeted throughout tumour development.

Endothelial cells and VEGF are genetically stable targets

The regulation and stability of important processes in tumourigenesis(The process of initiating and promoting the development of a tumour) is illustrated in this image.24,28–32

As observed in preclinical models, considerable variation may exist in the genetic stability of important antitumour targets. For example, kinase receptors on tumour cells may be susceptible to genetic mutation.33 Moreover, the process of tumour proliferation is mediated largely through autocrine signalling(A form of signalling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on the same cell, leading to changes in the cell), in which a tumour cell secretes an agent (such as EGF) that acts upon the same cell type.34 Genetic mutations within these cells may destabilise the pathway, potentially limiting the ability to continually target this process.28,29

In contrast, based on preclinical observations, it has been proposed that both the endothelial cell and VEGF are genetically stable.35 VEGF is part of a predominantly indirect paracrine signalling(A form of cell signalling in which the target cell is near the signal-releasing cell) pathway – the angiogenic pathway – in which the secretion of growth factors from tumour cells affects activity on nearby, yet distinct, endothelial cells.30–32,35 The stability of VEGF and the endothelial cells in non-cancerous cells makes continued targeting of this pathway an important antitumour strategy.

VEGF expression is continuous


In addition to being stable over time, VEGF is also continuously expressed throughout the development of many tumour types. In fact, VEGF is the only angiogenic factor known to be present throughout the entire tumour life cycle. As the tumour develops further, it may begin to activate secondary angiogenic pathways, such as those stimulated by bFGF(Mitogenic growth factor that is widely utilised during wound-healing, growth and development), TGFβ, PlGF and PD-ECGF(A substance contained in the alpha granules of blood platelets whose action contributes to the growth of endothelial cells in blood vessel walls). As these secondary pathways emerge, VEGF continues to be expressed by the tumour and remains one of the critical mediators of angiogenesis.2,24,25,31 Therefore, prolonged and continuous inhibition of VEGF may be necessary to effectively inhibit tumour growth, as demonstrated in pre-clinical models.36

Understanding tumour progression

Important differences among antitumour strategies

In light of the proposed ongoing effects of VEGF inhibition, it is important to consider the possible reasons for tumour progression, which may vary widely among different antitumour strategies. With agents that target the tumour directly, progression often occurs through mutational pathways, in which tumour cells that are less sensitive to therapy emerge and repopulate the tumour. As a result, the effectiveness of many tumour-targeting agents may diminish over time.27,33

With agents that target VEGF directly, tumour progression may develop through non-mutational pathways. Based on preclinical observations, it has been proposed that endothelial cells and VEGF are genetically stable.35 Therefore, escape from agents that directly target VEGF is generally not thought to occur through acquired resistance but rather through the activation of secondary pathways. Activation of these redundant pathways may occur as a compensatory response to treatment or as a result of tumour cell mutations (i.e. mutations that are not associated with direct VEGF inhibition).1,26,27,37,38 Because VEGF remains the predominant mediator of angiogenesis, one option to consider as tumours progress is to maintain precise VEGF inhibition and supplement it by selectively targeting other emergent pathways.1,27

Summary

VEGF is one of the most potent and predominant known pro-angiogenic factors and is both present and stable throughout the tumour life cycle. Preclinical evidence supports maintaining direct and continuous VEGF suppression over time. As tumours develop, continued VEGF suppression is thought to provide important ongoing antivascular effects that may inhibit further growth and spread of tumour cells. Therefore, one area of anti-angiogenesis research that is being pursued is the strategy of maintaining precise VEGF inhibition as tumours progress and supplementing it with selective targeting of other emergent pathways.

While there are multiple strategies for inhibiting the VEGF pathway, there are potential advantages to targeting VEGF directly. In particular, by specifically targeting VEGF, a VEGF antibody disrupts only the VEGF pathway, thereby avoiding unwanted inhibitory effects on non-VEGF-mediated functions. Based on preclinical models, it has been proposed that anti-VEGF agents exert both rapid and continuous antivascular effects, including regression of existing tumour vessels, an anti-permeability(Anti-permeability is the decrease in vessel permeability that results from the blockade of VEGF by anti-VEGF agents) effect in surviving mature vasculature and inhibition of both new and recurrent tumour vessel growth. Precise VEGF inhibition may also provide versatility to address changing tumour biology over time.

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