VARI Finds Key Cancer Mechanism

April 18, 2003
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GRAND RAPIDS — Scientists at the Van Andel Research Institute have uncovered two proteins that work in concert to trigger the spread of cancerous tumors, and are experimenting with a molecule that has the potential to block their interaction.

Scientists in the institute’s Laboratory of Cell Structure and Signal Integration discovered a regulatory circuit in cells that regulates cell architecture and movement. The circuit is made up of two proteins, Cdc42 and Drf3, which work like a tag team of molecular “switches.”

What researchers found was that when Cdc42 is activated, it attaches to Drf3, causing that protein to activate as well. When Drf3 is activated, it affects a cell’s internal structure, giving it shape and the ability to move.

“That’s what we actually discovered — the fact that this actually occurs,” said Arthur Alberts, Ph.D., who heads the lab. “Our educated guess was that these cells were moving and behaving a certain way. Was it because of the possibility that these two proteins were interacting? We tested that and, lo and behold, it was true.”

VARI scientists pinpointed the location on a cell where the two proteins interact to set the process in motion.

“The cell works like a computer chip; it’s full of networks of cells that interact with each other and use biochemistry to speak to each other,” he explained. “It’s exactly like the different switches that are thrown on a computer chip.”

Cdc42 interacts with another molecule known as GTP, the same molecule in DNA, which works in molecules like a signal. GTP floats around inside the cell and bumps into Cdc42 and causes it to literally switch its shape and then interact with Drf3, Alberts explained.

His team’s research suggests that if Cdc42 can be inhibited from binding to and activating Drf3 in a cancerous cell, it could halt the cell’s ability to migrate to other parts of the body and create new tumors.

Intercepting the two switches may not only immobilize the cancerous cell, but may also keep it from growing, Alberts said.

Since identifying the two proteins, his lab has been using a molecule called DAD to disrupt their interplay in tumor cells. Alberts discovered DAD two years ago, shortly after joining VARI.

The Drf3 protein is like a U-shaped molecule, with two arms that interact. DAD is one arm of Drf3. VARI experiments have shown that DAD can block the location where Cdc42 normally binds to Drf3 and, essentially, short-circuit the two switches.

Similarly, the drug Taxol, which is used to treat breast and other cancers, works by disrupting the cell’s internal structure or “cytoskeleton.”

Now the goal is to exploit the VARI discovery and try to develop novel anti-cancer drugs based on DAD, Alberts said.

“The exciting part, the real take-home message, is that if we can block these circuits composed of things like Drf3 and Cdc42, we have what is potentially a new class of anti-cancer compounds that do a lot more than what Taxol does.

“The problem right now is that DAD, because it’s a part of Drf3, you can’t get it in the cells. One of the big problems in drug development, the pharmacology aspect of it, is bio-availability,” Alberts said.

A lot of molecules can be discovered in a test tube, but the question is, how can they be directed to a targeted cell inside a patient? The pharmaceutical sector spends billions of dollars trying to get things that work in test tubes into people’s bodies, he observed. And often that becomes the roadblock to potentially exciting new drugs.

“We have identified this interaction and it’s fundamentally important. Since we know how DAD works, we’re going to try to discover new drugs that work like DAD or we’re going to make DAD better so it does work like a drug.

“One of the things that we’re looking for now is investment in trying to develop this. We already have DAD and the intellectual property on that. Now what we want to do is set up a high through-put screen to look for compounds that work like DAD.”

Potentially, the discovery has implications for any form of cancer, because it has also led VARI scientists to begin investigating the Drf gene family as potential cancer genes.

It turns out that Drf3 is part of a family of proteins found everywhere in living things.

“Why study these molecules in yeast cells and plant cells? It’s because you can do the genetics and the molecular biology to understand their function,” Alberts explained. “And since they’re structurally themed, more or less, we can take that information and throw it at disease problems that occur in men and women.”

Furthermore, when his lab uncovered the connection with Drf3, it found that it was disrupting a family member, Drf1, a gene that has mutated into a specific kind of hearing loss. Thus, the VARI discovery could have further implications for hearing and neurological disorders, as well.

“This is just the tip of the iceberg,” Alberts said. His ambition is to develop a DAD-like drug within the next five years, but that doesn’t mean that it would be in use in clinical trials within that time frame, he added.

The study, which appeared in the April 1 issue of Current Biology, was co-authored by VARI researchers Brad Wallar and Jun Peng. Pam Swiatek of the VARI contributed to the study, Alberts noted.

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