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• Stability of VEGF

VEGF is a genetically stable target

Regulation and stability of important processes in tumorigenesis^3-8,10

1. Tumor proliferation: mediated primarily through autocrine signaling pathways
   • A tumor cell secretes agents (eg, PDGF) that signal the same cell type
   • Instability of tumor cells limits the ability to continually target an autocrine pathway
2. Angiogenesis: a predominantly indirect paracrine signaling pathway
   • Secretion of growth factors (eg, VEGF) from the tumor affects cell proliferation and survival
   • Relative stability of ligand and receptors makes continued targeting of the VEGF pathway a viable antitumor strategy

As observed in preclinical models, considerable variation may exist in the genetic stability of important antitumor targets. For example, kinase receptors on tumor cells may be susceptible to genetic mutation.¹ Moreover, the process of tumor proliferation is mediated largely through autocrine signaling, in which a tumor cell secretes an agent (such as platelet-derived growth factor [PDGF]) that acts upon the same cell type.² Genetic mutations within these cells may destabilize the pathway, potentially limiting the ability to continually target this process.^3,4

In the example of the VEGF ligand, we find a genetically stable protein that is part of a predominantly indirect paracrine signaling pathway—the angiogenic pathway, in which the secretion of growth factors from tumor cells affects activity on nearby, yet distinct, endothelial cells.^3-9 The stability of the VEGF ligand and receptors in noncancerous cells makes continued targeting of this pathway an important antitumor strategy.

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