VARI Starts Cancer Drug Search

April 16, 2004
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GRAND RAPIDS — The Van Andel Research Institute has embarked on its first drug discovery program and hopes to develop novel anti-cancer drugs based on a discovery scientific investigator Arthur S. Alberts, Ph.D., made four years ago.

Alberts heads VARI’s Laboratory of Cell Structure and Cell Integration, where a team of six scientists studies the intracellular signaling networks that regulate cell proliferation, shape and movement in an effort to understand why and how cells succumb to disease.

Earlier this month, VARI received a $315,000 grant from the National Institute of Health (NIH) to fund the first two years of the drug discovery start-up program. The National Cancer Institute, the largest institute under NIH’s umbrella, is sponsor of the grant.

A year ago VARI’s Laboratory of Cell Structure and Cell Integration announced it had discovered a regulatory circuit in cells that regulates cell architecture and movement. The circuit is made up of two proteins that work like a tag team of molecular “switches” that trigger the spread of cancerous tumors. VARI scientists pinpointed the location on a cell where the two proteins interact to set the process in motion.

Since identifying the two proteins, the lab has been experimenting with a molecule that has the potential to block their interaction — a molecule called DAD that Alberts discovered in 2000, shortly after joining VARI.

DAD is a part of one of the larger proteins found in humans, animals, plants and fungi — proteins that are “absolutely critical” for the ability of cells to control their shape and size, and their ability to divide and respond to signals from the outside of the cell, Alberts explained. He said introducing DAD into certain types of cancer cells interrupts the cells’ ability to control their shape and metastasize, basically causing the two molecular “switches” to short out.

The goals of the drug discovery program are to determine which types of cancer cells respond best to DAD and to identify other compounds that work like DAD. Certain breast and prostate cancer cells have already proven sensitive to DAD, and VARI scientists intend to find out just how many other types of cancer cells will respond to DAD.

The team’s first aim is to analyze the structure of DAD and use that information to “design a better DAD or design a molecule from the ground up,” Alberts said. His lab will do that in collaboration with H. Eric Xu, Ph.D., senior scientific investigator in VARI’s Laboratory of Structural Sciences.

Alberts and another scientist in his lab will be dedicated to the drug discovery program for the next two years. They will start by fishing through the chemical libraries, looking for molecules that have activities similar to DAD.

There are a lot of very effective chemicals out there that will kill cancer cells, Alberts observed, but the difficulty is getting the drugs into the cancer cells.

“We have made a version of DAD that can get into cancer cells and we’re going to give it a go. We’re going to start screening on tumor cell lines and ask which ones will be sensitive to DAD.”

The last objective, he said, is to develop the ability to do the high throughput screening. That’s the point where the research team would start to look for new drugs that work just like DAD.

DAD has a net effect similar to that of Taxol, the anti-cancer drug used to treat breast cancer, Alberts noted. Taxol, however, has been associated with side effects that include heart damage, nerve pain and acute hypersensitivity, he pointed out. VARI scientists hope to develop a new anti-cancer therapy minus the Taxol-like side effects.

There are many companies that are developing new Taxols to get around the various side effects, and roughly 170 versions are currently being used to treat different cancers.

“The unfortunate thing is that they’re working with something that is essentially a safe bet,” Alberts said. “Taxol is a very effective drug and has saved a great many lives. But the work that they’re doing is essentially extending what we already know and is really not going to be leading us to anything that’s new.

“That’s one of the reasons we’re excited about the possibility of turning DAD into something that can work as an anticancer drug. If we are successful, this will represent an entirely new class of drug. There may be other aspects of it — that it may be applied to other diseases, as well.”

DAD and Taxol work by interacting with very different proteins. Taxol binds directly to the “building blocks” that maintain cell shape, he explained. By binding to an individual building block, Taxol stops its ability to assemble. DAD, on the other hand, controls the way those building blocks are assembled.

Upon conclusion of the project, he said, VARI will start to look at partnering with a large pharmaceutical firm or will begin to seek entrepreneurial funding or new government funding for actual development of a new drug.

VARI’s ambition is to develop a DAD-like drug within the next four to five years, but that doesn’t mean that it would be in use in clinical trials within that time frame, Alberts added.

Clinical trials and FDA approval would take more time.

“There are a huge number of hurdles you have to go through and usually getting over those hurdles is much easier if you have a huge amount of money,” Alberts noted. “It can take anywhere from five to 15 years. The regulations are constantly changing because they’d like to see drugs in the pipeline much faster, but you just never know.”

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