Dual-action protein better restricts blood vessel formation

In a paper published online Aug. 8 in the Proceedings of the National Academy of Sciences, researchers at Stanford University describe the creation of a new type of engineered protein that is significantly more effective at preventing the formation of blood vessels by targeting not one, but two of the chemical receptors that control the creation of new capillaries - a process known as angiogenesis. The study shows that the new protein blocks both receptors.

 

"Chemical receptors and their protein ligands control many cellular functions, but the protein must fit the receptor exactly. It's like a molecular jigsaw puzzle," said lead researcher Jennifer Cochran, PhD, assistant professor of bioengineering. "When the right proteins come along and engage their matching receptors, things begin to happen at the cellular level. In this case, we looked at the chemical signaling and cellular machinery responsible for producing new blood vessels."

 

Existing cancer treatments block the activity of specific receptors that control capillary creation. Some of these drugs act like a cork in a bottle, occupying the receptor and thus preventing capillary-inducing proteins from activating cell signaling and biochemical processes, while others attach to the capillary-inducing proteins and shield the receptor from them.

 

Complicating matters for cancer researchers, however, is the fact that angiogenesis is often controlled by multiple receptors working together. "Cell-signaling pathways are analogous to a safe-deposit box requiring many keys to open," said Cochran.

 

In such situations, receptors work in tandem, communicating back and forth in a chemical collaboration known as cross-talk. Current anti-angiogenesis therapies, however, are able to target only single receptors. Thus, significantly limiting capillary growth requires blocking more than one receptor.

 

Cochran's team — including postdoctoral scholars Niv Papo, PhD, Adam Silverman, PhD, and Jennifer Lahti, PhD, who was a graduate student at the time of the research — identified likely pairs of collaborating receptors. They knew from a body of earlier research that there was significant cross-talk between two specific angiogenic receptors. Their goal was to create a single protein that could block both.

 

First, the team selected a protein that bonds with one of the receptors. Using it as a molecular "scaffold" they affixed, or substituted, a new section that could bond with the second receptor, all without altering the original function or the physical structure of the larger scaffold protein. They succeeded; their new protein blocks both receptors.

 

Beyond cancer, Cochran noted, the prevention of angiogenesis could prove helpful in the treatment of diseases such as macular degeneration, one form of which can lead to visual impairment or even blindness when unchecked capillaries grow in the retina.

 

As for the scaffolding approach, she said she sees a research strategy that might be applied to develop new, multifunctional proteins that work in other biomedical applications, from diagnostics and immunotherapy to tissue repair.

 

"All the attention being accorded dual-action proteins is warranted," Cochran said. "Sometimes, two are better than one."