Replacing Bevacizumab: Using Aptamers to Inhibit the VEGF-A Pathway Ryan Lannan – Nucleic Aptamers Stream – Fall 2011

Vascular endothelial growth factor A is a glycosylated mitogen that acts on endothelial cells in order to promote angiogenesis, vasculogenesis, endothelial cell growth and inhibit cell apoptosis. But while VEGF-A serves a positive role in normal body function, it also can help malignancies in the body develop. In studies on cancer growth and development it’s been shown that while there are many pro-angiogenic factors, the VEGF-A ligand is the predominant mediator of tumor growth. In the early stages of tumor development, VEGF helps establish new vasculature, providing the tumor with an independent blood supply. As development continues, VEGF-A helps this vasculature to spread, allowing metastasis and further tumor growth. It then maintains this vascular network, helping it survive by inhibiting apoptosis. In essence, VEGF-A allows for cancers to develop and metastasize and contributes to their survival at all points during their life cycle.

It has been found that inhibition of the VEGF-A pathway may be a promising new antitumor strategy. By inhibiting the ligand, VEGF-A is not able to bind or interact with any of its receptors, VEGFR-1, VEGFR-2 or neuropilin-1. While inhibition of any of these receptors may cause a wider range of inhibitory effects beyond the VEGF-A pathway, inhibiting VEGF-A only inhibits the VEGF-A pathway, decreasing possible complications. This concept of targeting the VEGF-A ligand in order to inhibit tumor growth and metastasis is the basis of the new treatment Bevacizumab. Bevacizumab uses a humanized monoclonal antibody designed to target VEGF-A, and has been shown to prolong the life of patients with metastatic lung and breast cancers. Unfortunately the cost of producing Bevacizumab is extremely high, making the treatment cost $100,000 a year. If another cheaper method were found for inhibiting the VEGF-A pathway it would be groundbreaking. RNA ligands called aptamers can be used to inhibit protein function, binding with high specificity and affinity, and are cheaper, more efficient replacements for antibodies.

The selection of RNA aptamers against VEGF-A could be the first step in finding an RNA ligand that could inhibit the VEGF-A pathway, slowing the growth of tumors and preventing metastasis. If the nucleotide sequence was shared as part of the People’s Aptamer Project, then drug companies could develop a cheaper, more effective, replacement to the already existing drug Bevacizumab.

Figure 1: The interaction of the VEGF-A ligand with VEGFR-1, VEGFR-2 and nueropilin-1 lead to the development of vasculature which helps tumor development and can lead to metastasis.

1. Hicklin DJ, Ellis LM. J Clinical Oncology. 2005;23:1011-1027.

2. Presta LG, Chen H, O’Connor SJ, et al. Cancer Res. 1997;57:4593-4599.

Written by Ryan Lannan - Aptamer Stream Fall 2011