Common Antifungal Drug Shrinks Tumors

Date: Aug-21-2012An approved generic drug that has been in use for decades is showing promise as a treatment for cancer: in trials on mice it shrank tumors by
disrupting their blood supply.

Thiabendazole is a generic, FDA-approved, inexpensive antifungal drug that can be taken orally and has been in clincal use for over 40 years. The drug is not
currrently used to treat cancer.

Scientists from the University of Texas at Austin discovered the drug's potential to treat cancer almost by accident while looking for evolutionary links in yeast,
frogs, mice and humans.

Hye Ji Cha, Edward Marcotte, John Wallingford and colleagues describe the drug's capacity as a "vascular disrupting agent" that destroys newly-established blood
vessels in a report due to be published online in the journal PLoS Biology.

As tumors develop, they grow their own network of blood vessels to fuel their uncontrolled growth.

So anything that starves tumors of their blood supply is worth investigating as a potential chemotherapy.

In trials on mice, thiabendazole decreased blood vessel growth in fibrosarcoma tumors by more than 50%, and it also slowed the growth of the
tumors. Fibrosarcomas are cancers of the connective tissue, and they generally have a strong network of blood vessels.

In a statement to the press this week, Marcotte said this was an exciting discovery, because "in a way we stumbled into discovering the first human-approved vascular disrupting
agent."

"Our research suggests that thiabendazole could probably be used clinically in combination with other chemotherapies," he added.
The Discovery Crossed Disciplines and Organisms
The discovery was a journey that crossed disciplines and organisms.

In an earlier study, Marcotte, a professor of chemistry, and his team had already pinpointed genes that because of their shared evolutionary paths, were common
to single-cell yeasts and creatures with backbones (vertebrates).

In yeasts, which have no blood vessels, the genes control the cell's response to stress.

In vertebrates, the genes have evolved a new role: they control angiogenesis, the process that forms new veins and arteries.

Marcotte said they had a hunch if they analyzed these genes, they might be able to find drugs that target this gene pathway in yeast that also work as
angiogenesis inhibitors.

First they looked for a molecule that would inhibit the action of the genes in yeast, and that's when they came across thiabendazole and tested its effect in vertebrate biology.

The drug inhibited blood vessel growth in developing frog embryos and also the development of human blood vessels grown in the lab.

After that, they did the trials in mice with fibrosarcoma tumors and found the drug reduced their blood supply and shrank them.

Wallingford, an associate professor of developmental biology, said:

"We didn't set out to find a vascular disrupting agent, but that's where we ended up."

"This is an exciting example of the power of curiosity-driven research and the insights that can come from blending disciplines in biology," he
added.

The team is now talking with clinical oncologists about testing thiabendazole as a cancer therapy in clinical trials with humans.

Marcotte anticipates this step will be more straightforward than with a new drug, because thiabendazole has already been approved by the FDA for human
use.

Funds from various organizations, including the Howard Hughes Medical Institute, the Cancer Prevention Research Institute of Texas, the Welch Foundation, and
the National Institutes of Health helped pay for the study.

Written by Catharine Paddock PhD

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