Driven by potential

by David Rumbach

ND chemist studies compound he invented to treat stroke, cancer

SOUTH BEND — A molecule invented by a University of Notre Dame chemist has been shown to reduce brain damage from stroke and slow down cancer in recent experiments performed on mice.

University of Notre Dame chemist Shahriar Mobashery invented the compound, called SB-3CT, four years ago while he was a professor at Wayne State University and has continued to work on it over the past two years at ND.

Evidence for the compound’s effectiveness in mice — a clue but by no means a guarantee that it will work in people — has been boosted by two recent studies.

In July, a study based on research done in California showed that SB-3CT reduced brain damage in mice that had suffered strokes.

A month earlier, researchers in Germany reported that it had extended survival in mice with an aggressive form of lymphoma.

Mobashery said the studies show that SB-3CT deserves to be taken to the next level of drug development. That includes further animal tests to see exactly how the compound is metabolized and to gauge its toxicity.

“I’m personally committed to move this as far as I possibly can,’’ Mobashery said, noting that all of the research leading up to human trials can be done at ND.

Mobashery, who holds a patent on SB-3CT, said the molecule inhibits two naturally occurring enzymes, called gelatinases, that are culprits in a variety of diseases.

In ischemic strokes, the kind caused by clots that cut off blood flow to part of the brain, gelatinases are believed to promote the death of brain cells.

In cancer, Mobashery said they allow cancer cells to break away from tumors, freeing them to enter the bloodstream and spread throughout the body.

The only current treatment for ischemic stroke is a clot-busting drug (t-PA) that must be given within three hours of the onset of symptoms. Most people having strokes aren’t taken to the hospital quickly enough to receive it.

But the tests in California found that SB-3CT had a beneficial effect in mice brains up to six hours after the start of stroke. That implies that SB-3CT, if it works in people, might provide a larger window of opportunity for them to get to the hospital and receive treatment.

Tests at the Burnham Institute in LaJolla, Calif., showed that it reduced tissue loss in mice brains by 70 percent. The study appeared in the Journal of Neuroscience.

The cancer study in Germany involved mice that had been genetically altered to develop a very aggressive form of lymphoma. SB-3CT slowed liver metastasis in these mice and extended their survival by 30 percent to 40 percent, according to a study in the May edition of the journal Cancer Research.

But a senior principal investigator at the National Cancer Institute expressed some doubt about the promise gelatinase inhibitors may hold in stopping cancer.

Dr. William Stetler-Stevenson, a senior principal investigator in NCI’s cell and cancer biology branch, said the strategy was extensively studied in the 1990s — with discouraging results. The approach worked well in mice, but benefits were not seen in people, he said.

“We’ve been down this road,’’ he said.

Mobashery said earlier drug studies involved substances that inhibited a whole class of enzymes called matrix metalloproteinases. They were "broad-spectrum’’ in their effect.

His molecule is different in that it inhibits only two — MMP-2 and MMP-9 — that he and other scientists believe are involved in cancer metastasis. So far, he said, SB-3CT is the only chemical proven to be selective against that pair.

Stetler-Stevenson, however, said that while he believes that MMP-2 and MMP-9 are culprits in stroke and heart attack, they may not be the most important targets in cancer.

“There is a significant amount of evidence that other MMPs may be better targets in respect to cancer,‘’ he said. "But in stroke and cardiac disease they may play an important role.’’

Only more research, time-consuming and costly, will determine whether SB-3CT will give doctors new weapons and against what diseases.

TopicID: 14503