A cancer drug called bexarotene failed to live up to its early promise in treating the brain plaques of Alzheimer’s disease, though the drug did show some benefits in improving memory in animal studies. The mixed findings highlight the difficulty of developing effective new therapies for a disease that affects more than 5 million Americans and more than 25 million worldwide.
Bexarotene, which goes by the brand name Targretin, had generated some excitement in 2012 following a study published in the prestigious journal Science that found that it appeared to improve memory and, within days, break up brain plaques in mice that had been bred to develop a disease that resembles Alzheimer’s in people. The plaques, formed by a sticky protein called beta-amyloid, are a hallmark of Alzheimer’s, and researchers have long been seeking to find effective therapies to prevent or reverse their buildup.
But in follow-up testing among different research groups, scientists could not replicate the initial results, an important step in the scientific process. The drug didn’t seem to have any significant effect on brain plaques in three different strains of mice. It also has some serious side effects, including thyroid, liver and blood abnormalities, pancreatitis and digestive upset, headaches, depression and fatigue. Because of the potential dangers, several of the scientists recommended that bexarotene not be tested further in people.
"Science is a learning process, and one learns by trial and error and by starting again and correcting mistakes,” said European researcher Bart De Strooper, head of the VIB Department of Molecular and Development Genetics in Leuven, Belgium and the author of one of the papers. “This is the only way that we can learn from our mistakes and hopefully one day develop a drug."
Kevin Felsenstein of the University of Florida, a co-author of one of the follow-up papers, said he was surprised by the earlier claims that “with as little as three days of treatment, they basically cleared the amyloid deposits from these animals,” something that did not pan out in he and his colleagues’ follow-up study. “These deposits have been described by some as cement, and it will take a lot to get rid of them.”
In a separate report from researchers at the University of Pittsburgh, though, bexarotene was found to quickly reverse memory problems in mice that had been genetically altered to develop an Alzheimer’s-like illness. The mice were, for example, able to remember the location of a hidden underwater resting platform after being given the drug. The researchers did not, however, find any evidence that the drug cleared plaques from the brain.
“It is possible that the improvement of cognitive skills in mice treated with bexarotene is unrelated to beta-amyloid and the drug works through a completely different, unknown mechanism," said senior author Dr. Rada Koldamova, an associate professor at Pitt Public Health's Department of Environmental and Occupational Health. “"We believe these findings make a solid case for continued exploration of bexarotene as a therapeutic treatment for Alzheimer's disease."
Bexarotene is similar in chemical structure to vitamin A. It is currently approved by the Food and Drug Administration to treat a form of skin and immune cell cancer called cutaneous T cell lymphoma. Though doctors could technically prescribe it off-label for Alzheimer’s, it has serious side effects, and its effects on the brain, as these latest studies make clear, and not well understood. Bexarotene has never been tested as a treatment for Alzheimer's disease in people, so the optimal dose or duration of treatment, or whether it is even effective, remains unknown.
"Anecdotally, we have all heard that physicians are treating their Alzheimer's patients with bexarotene, a cancer drug with severe side effects," said co-author Robert Vassar, professor of cell and molecular biology at Northwestern University Feinberg School of Medicine and the author of another of the papers, which were like the original report also published in Science. "This practice should be ended immediately, given the failure of three independent research groups to replicate the plaque-lowering effects of bexarotene."
Sources: "Technical comment on ApoE-Directed Therapeutics Rapidly Clear b-Amyloid and Reverse Deficits in AD Mouse Models," Ina Tesseur et al., Science 2013