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Lawrence Marnett, Ph.D.

NIH grant bolsters search for new cancer drugs

BY: BILL SNYDER

10/16/2009 - Researchers at Vanderbilt University Medical Center have received a two-year, $4.7 million “Grand Opportunities” stimulus grant from the National Institutes of Health to launch a ground-breaking cancer drug discovery program.

The Vanderbilt Molecular Target Discovery and Development Center, a joint effort of the Vanderbilt Institute of Chemical Biology (VICB) and the Vanderbilt-Ingram Cancer Center, initially will hone in on “triple-negative” breast cancer, a particularly deadly form of the disease.

Researchers will try to identify genes that are the “drivers” for the different subtypes of triple-negative breast cancer, and then fashion drugs to block the action of the proteins encoded by the genes, with the intent of killing the cancer cells.

“The beauty of this approach is that if you end up with drugs at the end of this whole process, you already know which patients should get them,” said VICB director Lawrence Marnett, Ph.D., and the grant's principal investigator.

“This is really personalized drug discovery,” said Marnett, University Professor, Mary Geddes Stahlman Professor of Cancer Research, and director of the A.B. Hancock Jr. Memorial Laboratory for Cancer Research. “We think (it) represents the model for the future.”

The most successful treatments for breast cancer target tumors that “express” receptors for the hormones estrogen and progesterone and the human epidermal growth factor receptor 2 (HER2).

Because “triple-negative” breast cancers don't express these receptors, they are difficult to treat. They account for 25 percent of all breast cancer deaths, and disproportionately affect African-American women.

In laboratory studies, Jennifer Pietenpol, Ph.D., director of the Vanderbilt-Ingram Cancer Center, Carlos Arteaga, M.D., who directs the center's breast cancer program, and David Cortez, Ph.D., associate professor of Biochemistry and co-director of the center's genome maintenance program, will use a technique to “knock out” cancer genes one at a time.

The idea is to find the cancer's “Achilles heel,” the gene most likely to be blocked by a drug.

Stephen Fesik, Ph.D., a professor of Biochemistry recruited this year from Abbott Laboratories, will express the protein encoded by this gene. Then he will use a nuclear magnetic resonance (NMR)-based screening technique he developed to find a site on the protein to which a drug might bind.

David Weaver, Ph.D., who directs the VICB high-throughput screening facility, will try to identify small molecules that bind to and inhibit the protein.

Marnett predicted that by the end of the two years of the grant, “we will have built a platform to identify the best potential targets for triple-negative breast cancer.”

Developing and proving the safety and efficacy of a new drug will take more time, “but we will definitely have leads that could be moved through very quickly if they look exciting,” he said.

The cancer drug discovery grant is part of the “Grand Opportunities” program funded by federal stimulus money.

Funded through the National Cancer Institute and the NIH director's office, it is one of three Grand Opportunities grants received by Vanderbilt researchers this year.

See related story here.

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