Science

Failed cancer drug may find second life targeting Alzheimer's and dementia

Failed cancer drug may find se...
An illustration showing how abnormal tau protein tangles (in orange) can accumulate and destroy neurons, resulting in cognitive degeneration associated with diseases such as Alzheimer's
An illustration showing how abnormal tau protein tangles (in orange) can accumulate and destroy neurons, resulting in cognitive degeneration associated with diseases such as Alzheimer's
View 1 Image
An illustration showing how abnormal tau protein tangles (in orange) can accumulate and destroy neurons, resulting in cognitive degeneration associated with diseases such as Alzheimer's
1/1
An illustration showing how abnormal tau protein tangles (in orange) can accumulate and destroy neurons, resulting in cognitive degeneration associated with diseases such as Alzheimer's

Compelling research, led by a team from the University of California, Santa Barbara, has discovered a drug originally developed as a cancer treatment may be repurposed to target a variety of neurodegenerative diseases including Alzheimer's. Despite proving to be ineffective in treating cancer, the new drug has been shown to be safe for humans and early mouse studies suggest it could have potential as a new dementia treatment.

Alzheimer's research has undeniably been in a major state of flux over the past few years. Just last week yet another major drug failed in late stage human trials after years of work and millions of dollars of funding. Almost every major Alzheimer's drug failure over the years has targeted the accumulation of a protein in the brain called beta-amyloid.

The amyloid hypothesis has dominated Alzheimer's research for a couple of decades now, however, every drug designed to target the accumulation of these toxic proteins has failed at some stage in human testing. Researchers have also studied another protein called tau thathas been found to accumulate in the brains of Alzheimer's sufferers.

Misfolded tau proteins, called neurofibrillary tangles, tend to appear in the brains of people with Alzheimer's much later than amyloid plaques, although there are other neurodegenerative diseases known to be entirely driven by the accumulation of these tau tangles.

Kenneth Kosik, co-director of the Neuroscience Research Unit at UC Santa Barbara, has been investigating the associations between tau and neurodegenerative diseases for several decades. The latest study published by Kosik and his collaborators is the culmination of years of work leading to an understanding of what specific genes and proteins guide the formation of abnormal tau tangles in the brain.

Prior research had revealed that a specific protein called Rhes was abnormally activated in patients suffering from genetic mutations that result in tau-related neurodegenerative disease. This led the researchers to look at a drug that had already been developed to inhibit the activity of that specific protein.

"It turns out the drugs in this category, called farnesyltransferase inhibitors, have been tested in humans," says Kosik. "They're safe. But, they did not work in cancer."

Called lonafarnib, the drug was originally designed to interrupt tumor growth in a variety of cancers but human trials found it to be relatively ineffective for that purpose. Hypothesizing the drug to potentially be effective in disrupting the process that causes tau tangles, the researchers embarked upon a series of mouse experiments that provided dramatically positive results.

"To test this drug we used genetically engineered mice that develop human tau tangles and then dementia," Kosik explains in commentary penned for The Conversation. "Such animals often run in circles. But when we fed these animals lonafarnib, the drug blocked the formation of the tau tangles in the brain and the abnormal behavior. When tau tangles disrupt the normal brain activity, the mice are unable to build nests. But the mice receiving the drug proceeded with nest-building and other normal behaviors. Mice that were untreated all developed dementia."

Of course, the story of Alzheimer's research is littered with a near-constant parade of promising animal studies that simply haven't be replicated in human trials. So while this is an exciting piece of research, Kosik and his team are well aware of the challenges ahead.

Perhaps the biggest hurdle the researchers currently face is obtaining more lonafarnib so human trials can commence. Eiger BioPharmaceuticals, the company behind the drug, are reportedly reticent to make the drug available for Kosik's research. The company is primarily working through trials using the drug to treat progeria, a rare genetic condition that causes children to rapidly age.

Kosik and his team are currently trying to access more lonafarnib to continue their research.

The new research was published in the journal Science Translational Medicine.

Source: UC Santa Barbara

3 comments
Wombat56
The drug company's reluctance to supply is puzzling considering that Alzheimers must be a much larger potential market than progeria.
usugo
That comment about the drug availability is suspicious at best. The chemical is available from chemical suppliers and is relatively inexpensive. They bought the chemical for the study from one of these companies. And Eiger Bio doesn't seem to own the molecule. Only reason I can think of, they are trying to cut a deal to get the molecule for free. In addition, as usual, the amount used in mice during the experiments is exceedingly high, 4g/50Kg daily
ljaques
Big Pharma is all about money. Perhaps they're thinking "Who cares if anyone dies needlessly if we can make millions feigning concern." If they were fair, they'd price the same drugs the same price everywhere, but instead, they gouge the crap out of Americans and sell the same compounds for dirt cheap to the entire rest of the world. Plus, they may feel that if they give the lonafarnib to researchers, they might lose the extreme pricing for the new drug it creates when they do successfully utilize it. What has this world become? Human-up, people!