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What are the strategies for inhibiting the VEGF pathway?

There are 2 primary strategies for inhibiting the VEGF pathway

While VEGF is a predominant mediator of angiogenesis, there are different strategies for inhibiting its pathway. The 2 primary strategies include inhibiting either the VEGF ligand or the VEGF receptor (Fig. 1).¹

Fig. 1. Strategies for inhibiting the VEGF pathway¹

1. Some anti-VEGF strategies target the ligand, allowing for specific inhibition of the VEGF pathway.
2. Other strategies target the receptor. Some of these approaches (eg, TKIs) have a wider range of inhibitory effects beyond the VEGF pathway.

Extracellular targeting of the VEGF ligand

Anti-VEGF strategies that directly target the VEGF ligand include ligand-binding antibodies and soluble receptors. These agents work extracellularly to provide specific inhibition of the VEGF pathway and may therefore inhibit angiogenesis without disrupting other non-VEGF−related or “off-target” pathways.^2-4

VEGF also promotes angiogenesis by signaling through neuropilin, a co-receptor to VEGFR-1 and -2 on endothelial cells. The presence of neuropilin is associated with tumor aggressiveness and poor prognosis. Neuropilin receptors lack a targetable intracellular kinase domain. Therefore, anti-VEGF strategies that target the ligand extracellularly may be capable of attenuating VEGF signaling that is mediated through neuropilin (Fig. 2).^1,5-8

Fig. 2. Extracellular targeting of the VEGF ligand may inhibit signaling through both VEGF and neuropilin receptors on endothelial cells^1,5-8

Neuropilin receptors lack an intracellular kinase domain but are able to induce signaling by recruiting ligands to the cell membrane. There is also evidence to suggest that neuropilin may be able to transduce VEGF signals in the absence of tyrosine kinase VEGF receptors. Accordingly, prevention of neuropilin-mediated signaling may require an extracellular strategy of VEGF inhibition.

Considerable variation exists in the level of binding affinity among agents that target the VEGF ligand directly. In particular, soluble receptors have been observed to have a higher affinity for VEGF than monoclonal antibodies. In preclinical models, attempts to make molecules with higher VEGF binding affinity have not yielded an improved antitumor effect.⁹

Intracellular targeting of the VEGF receptor

Anti-VEGF strategies that target the VEGF receptor include TKIs and receptor antibodies. Agents that target the VEGF receptor intracellularly, such as TKIs, have a wider range of inhibitory effects beyond the VEGF pathway and may inhibit other pathways that are also mediated through receptor
kinases (Fig. 3).^2,4,10,11

Fig 3. Specificity of strategies targeting the VEGF pathway^12-14

Evidence also suggests that the specificity of an agent may impact its ability to target any one pathway. In particular, while agents that work broadly may be capable of inhibiting multiple pathways, their ability to inhibit activity through individual pathways and receptors may vary.^15,16

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Ellis LM, Hicklin DJ. Nat Rev Cancer. 2008;8:579-591.

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Lee D, Heymach JV. Clin Lung Cancer. 2006;7:304-308.

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Karaman MW, Herrgard S, Treiber DK, et al. Nat Biotechnol. 2008;26:
127-132.