Cancer drug points way to new Alzheimer’s approach

An altered version of the cancer drug Gleevec could form the basis of a new class of drugs that block the development of brain-damaging plaques in Alzheimer’s disease, U.S. researchers said on Wednesday.

They said they hoped drugmakers could tinker with the formula for Gleevec, a pill that has transformed the treatment of one type of leukemia, to make it work safely in the brain.

The key lies in an enzyme that triggers the production of beta amyloid plaques, one of the hallmarks of Alzheimer’s. Gleevec, now used to treat chronic myeloid leukemia, blocks this gamma-secretase activating protein.

“Our findings reveal that gamma-secretase activating protein is a potential target for a new class of anti-amyloid therapies,” said Paul Greengard, winner of the 2000 Nobel Prize for research into how neurons communicate, who worked on the study published in the journal Nature.

In prior work, Greengard discovered that Novartis AG’s Gleevec or imatinib blocks gamma-secretase activating protein.

The latest study, led by Gen He, a researcher in Greengard’s lab, shows that this protein dramatically increases the production of beta amyloid, and blocking the protein in genetically engineered mice kept Alzheimer’s brain plaques from developing.

Greengard said Gleevec clears too quickly from the brain to prevent Alzheimer’s disease on its own, but he believes drug companies could find ways to make it active in the brain longer.

“The development of compounds that work like Gleevec, but have the ability to pass the blood-brain barrier and target gamma-secretase activating protein could revolutionize the treatment of this disease,” Greengard said in a statement.

He said Gleevec could be modified chemically so it does not get pumped out right away. “I’m sure when our paper is published, a number of pharmaceutical companies will try to do just that,” he said.

MORE TARGETED APPROACH

Greengard said the gamma-secretase activating protein is more targeted than other Alzheimer’s drugs in development that target gamma-secretase. That is because it does not interfere with Notch, a vital cell signaling pathway that plays a pivotal role in the development of blood-forming organs and the immune system.

This new approach may sidestep some of the challenges seen with Eli Lilly’s recently failed phase 3 trial of its gamma-secretase blocker semagacestat, a drug that interfered with Notch signaling

“It’s known that gamma-secretase not only makes beta amyloid, but it makes many other substances that are vital for the survival of our cells,” Greengard said.

Alzheimer’s patients given the Lilly drug in a clinical trial actually developed worse symptoms, and were more prone to develop a form of skin cancer.

Alzheimer’s, a fatal disease that affects 26 million people globally, offers a tantalizing market to drug companies, but so far it has proven to be an elusive target.

Current drugs only treat symptoms, but no drugs can arrest the steady mental decline that robs victims of the ability to think and care for themselves.

SOURCE:  Nature, September 2, 2010.