Novel ligand peptide-mimic inhibits abnormal overgrowth of blood vessels, may lead to new anti-cancer drugs

UNM Comprehensive Cancer CenterOct 15 2015

An international research team led by scientists at the University of New Mexico Cancer Center discovered and developed a novel ligand peptide-mimic that inhibits abnormal overgrowth of blood vessels in retinal diseases and tumors. The discovery could lead to new drugs that keep cancers from growing. The team published a paper in the journal Science Translational Medicine.

The new drug candidate, named Vasotide™, is a cyclic peptide-mimic, which is a small chain of non-natural amino acids linked together.

The team has previously used an advanced high-throughput screening technique called phage display to discover a small peptide that ultimately was chemically modified to become Vasotide. Vasotide, they found, keeps a protein called vascular endothelial growth factor, VEGF, from binding to two different kinds of receptors on the surface of endothelial cells. Endothelial cells line the inside of blood vessels of normal organs and tumors. Therefore, in essence, Vasotide targets dual VEGF receptors that are central to the process of abnormal angiogenesis in malignant tumors and retinal diseases (such as age-related macular degeneration, diabetic retinopathy, and retinopathy-0f-prematurity).

Normally, when VEGF binds to one of its receptors the binding causes endothelial cells to multiply, allowing blood vessels to form. Preventing VEGF from binding to its receptors keeps excessive blood vessels from growing in disease settings such as tumors and retinal diseases.

The team tested its Vasotide in mouse and non-human primate models that mimic human eye diseases caused by out-of-control blood vessel growth. They were able to stop the abnormal blood vessel growth by giving Vasotide-containing eye drops.

Because tumors hijack blood vessels to develop their own abnormal supplies of oxygen and nutrients, the team is hopeful that Vasotide may be developed into an anticancer drug; indeed, previous work published in 2010 from Arap and Pasqualini has showed that a mouse model of breast cancer also responds to Vasotide.

"Vasotide represents the culmination of 15 years of translational work from ligand-receptor discovery to structure-function relationship to pre-clinical proof-of-concept in rodent and primate models. It may seem like a long time but it is actually warp speed in terms of drug development," says Arap.

Pasqualini says, "The fact that Vasotide may be delivered as eye drops rather than painful and cumbersome intra-ocular injections addresses a major unmet need in retinal diseases mediated by abnormal blood vessel formation. Indeed, with the aging of the baby boomer generation and the obesity epidemic, there has been a sharp increase in blinding caused by potentially treatable conditions such as macular degeneration and diabetic retinopathy."

Sidman says, "In this period of easy communication, it is worth noting that this research was carried out by well-coordinated investigators variously skilled in cell biology, medical practice, neuroscience, retinal biology, biochemistry, and animal disease model studies, some of the team members located initially in Houston and later in Albuquerque, and others in Boston, Hopkinton, St. Kitts, and São Paulo."