Discovery of unsuspected flexibility offers new pathway to cancer drug development

The University of Illinois research team also included graduate students Spencer Mamer and Si (Stacie) Chen, as well as other members of Imoukhuede's laboratory group. Their work examined two distinct signaling systems within the body that influence blood vessel growth and discovered that molecules from one system were able to interact with molecules from the other. The work was published in Scientific Reports.

"If we learn how the proteins fit together and cause protein function, then you can imagine that drugs can be developed that block the way things fit together and other drugs can be developed that enhance how things fit together," said Imoukhuede, who is also a member of the Carl R. Woese Institute for Genomic Biology. "Unlocking this understanding would lead to better drug design for treating several diseases including cancers and even cardiovascular diseases."

Many aspects of development and growth are regulated by growth factors, molecules produced by the body that direct tissue growth and encourage cells to divide. Each type of growth factor plays a unique role in specific tissues and phases of development, and this individuality of function is reflected in individuality of form: the particular three-dimensional shape of each type of growth factor allows it to interact with a specific set of receptors, molecules that coat the surface of cells and translate external signals into internal ones. This interaction is called binding.

Two different growth factors, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), are known to play important roles in blood vessel growth. Drugs that influence the signaling activity of each of these molecules have been used to treat various disorders. In particular, drugs that influence VEGF signaling have been a major focus of cancer therapies.

"Many anti-VEGF drugs including Avastin [a drug used to treat a variety of cancers] have failed due to drug resistance, which makes treatment ineffective and difficult to manage," Chen said. "Our initial research question was to better understand how tumor microenvironment develops resistance towards anti-angiogenic drugs, and eventually build better models to predict drug efficacy."

The group realized that drug resistance, as well as lesser efficacy in some individuals, might be explained if the body were somehow able to compensate for the loss of one type of signal by replacing it with another, similar one. The researchers recalled a study showing that VEGF can sometimes interact with receptors for PDGF. What if PDGF did something similar, attaching to VEGF receptors and acting like a second-string football player, keeping the game going in the absence of the starting athlete?

Imoukhuede and her coauthors tested their idea by examining the strength of every combination of paired interactions between the two growth factors and their families of receptors. Because of indications from past research that the two growth factors might be flexible in their partnering with receptors, they were not surprised to see that PDGF could form a bond with one of the VEGF receptors. What did surprise them was the strength of that chemical attraction.

"Cross-family binding has kind of been observed, but it's seen as very weak, the molecule is not the same, it doesn't fit in well, so it's never a tight binding to that receptor," Mamer said. "We would have imagined it orders and orders of magnitude weaker, and some of the interactions that we did find were almost at the level of VEGF itself, which meant that they could be very clinically significant."

These findings are in part a reminder that molecules are in no way bound by the names we give them. Names for cellular products are often chosen based on the context in which they were first discovered; while this system has some advantages, it can also lead to unconscious bias in what hypotheses are developed around those molecules and their functions.

"While people can be flexible in their thinking, I think these names often cause people to not explore the possibility that these are all similar proteins," Mamer said. "If we weren't worrying about their names too much, maybe we would be looking more for these interactions across [different signaling systems]."

The group hopes that exploring these types of complexities in growth factor signaling will eventually contribute to the development of more effective therapies either to promote signaling to aid recovery from conditions such as injury or stroke, or to inhibit it to block tumor growth. The next step toward this goal is to discover the functional results of cross-binding between the VEGF and PDGF signaling systems.

"Just because two molecules interact doesn't mean this actually can induce the changes in structure that are necessary for all the signaling events that come out of it," Mamer said.

"The next goal is to determine if the binding leads to protein activity, and if so to measure how much activity we see and how that leads to cell growth and cell movement," Imoukhuede said. "We eventually want to determine if this 'second string' can perform as well as our starters, and to fundamentally determine whether they are playing the same game."