Alzheimer's Drugs May Fight Rare Leukemia

Seek out enzyme that's key to both diseases

By E.J. Mundell HealthDay Reporter

Updated on June 14, 2022

THURSDAY, Oct. 7, 2004 (HealthDayNews) -- A breakthrough in finding better treatments against a rare childhood leukemia has gotten a big boost from research in a completely different field -- Alzheimer's disease.

Scientists believe the inhibition of a key cellular enzyme could lead to safe, effective treatments for both killer diseases. What's more, Alzheimer's researchers have already developed drugs targeting the enzyme, called gamma secretase. That means children with T-cell acute lymphoblastic leukemia (T-ALL) could be enrolled in clinical trials as early as next year.

"Usually, when you make a discovery like this and there's no drug, it would take a decade to get to the point where you might be able to test them in clinical trials. But we should be able to test them very, very quickly," said lead researcher Dr. Jon C. Aster, an associate professor of pathology at Brigham and Women's Hospital and Harvard Medical School.

The findings are a "win-win situation" for both T-ALL and Alzheimer's patients, added Alan Kinniburgh, senior vice president of research for the Leukemia & Lymphoma Society.

For those with T-ALL, gamma secretase inhibitors might someday replace current therapies, which work in only 75 percent of patients and come with serious side effects, he said.

And for Alzheimer's patients, it could speed research into proving these drugs work against a disease that affects millions.

"Because Alzheimer's takes many years to develop, it's difficult to know whether your drug is effective or not," Kinniburgh explained. If gamma secretase inhibitors prove effective against faster-moving T-ALL, "you're then able to say, 'This drug is effective in this disease; it therefore should be effective in Alzheimer's.'"

The findings appear in the Oct. 8 issue of Science.

Kinniburgh estimates that up to 1,000 Americans, mostly children and adolescents, are affected by T-ALL, an aggressive blood cancer that is fatal if left untreated. He described current chemotherapy against the illness as an effective -- but toxic -- strategy with painful side effects.

What's needed, Kinniburgh said, are more targeted treatments that fight cancer cells without harming healthy tissues.

Aster's team built on previous research that linked mutations in a particular gene, called NOTCH1, to the formation of T-ALL in mice. Mutant NOTCH1 appears to speed the replication of immune white blood cells, Aster explained, and about half of all T-ALL patients carry mutations in this gene.

The gamma secretase enzyme is key to this replication process, and in this latest study, compounds that inhibited its activity were shown to "prevent NOTCH-1 activity in T-ALL cancer cell lines, causing some of those cell lines to stop growing and die," Aster said.

Fortunately for T-ALL patients, gamma secretase inhibitor compounds are readily available, thanks to research into the enzyme's role in Alzheimer's disease.

"Gamma secretase is one of the components that cleaves a protein in amyloid plaque, seen in the brains of Alzheimer's patients at autopsy," explained Kinniburgh. "Amyloid plaque are the globs of goo in brain tissue that wind up being very toxic to the cells of the brain in Alzheimer's."

Based on those findings, Alzheimer's researchers have been hard at work developing drugs that inhibit the enzyme's protein-splitting activity, in the hopes that these compounds might slow or stop disease progression.

Aster said research into the NOTCH1 gene and gamma secretase inhibitors might have even wider applications.

"There's a suggestion that NOTCH1 might be involved in other forms of human cancers," he said. "So one thing we're doing, right at this minute, is looking at many, many other kinds of human cancers."

As for T-ALL, clinical trials using gamma secretase inhibitors could get under way as early as next spring, he said.

Kinniburgh called the findings a "milestone in T-ALL research," although he cautioned that drugs that fight cancer in a test tube sometimes fail in human trials. "These are wonderful first steps," he said, "but there's a long road to a drug that can treat a patient, leave that patient healthy, and not have side effects."

However, because of its fine-tuned targeting of mutant NOTCH1 functioning, Aster and Kinniburgh remain hopeful these enzyme inhibitors may fight T-ALL with minimal harm to normal cells.

"The model that everyone hopes to match is Gleevec, the drug that was developed for chronic myelogenous leukemia," Aster said. "It has turned out to be a remarkably gentle treatment with very few side effects. People take it as a pill, and it's quite effective."

More information

To learn more about T-cell acute lymphoblastic leukemia, visit the National Cancer Institute.

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