Repurposing a Cancer Drug for Alzheimer's? Not Just Yet

The cancer drug bexarotene (Targretin) has shown dramatic effects on Alzheimer’s-like symptoms in a mouse model, but it is too early to prescribe it for humans with Alzheimer’s.

Study results indicating that a cancer drug produced dramatic improvement in mice with Alzheimer’s disease (AD) symptoms touched off a great deal of interest in communities interested in AD. The study was published in the March 23, 2012, edition of Science.

The researchers hypothesized that bexarotene (Targretin)—an oral retinoid that has been FDA-approved for cancer since 2000—might activate retinoid X receptors on brain cells. This activation could increase concentrations of apolipoprotein E, a fat-protein complex that removes excess amyloid in the fluid-filled space between neurons. The team also determined that bexarotene might convert microglia into their alternative activation state, allowing amyloid beta (Aβ) phagocytosis.

The researchers administered bexarotene orally to mice genetically engineered to produce toxic Aβ peptides—protein fragments implicated in AD. Aβ plaques were reduced in the mice by greater than 50% within 72 hours, a result considered very unusual. The mice also improved cognitively and socially; those that had lost the ability to build nests resumed that activity. The mice’s AD-related olfactory deficits were also reversed. Bexarotene reduced plaques by as much as 75% after 14 days, but the mice’s plaque burden (but not more toxic soluble Aβ peptide) grew to a burden similar to control mice after 3 months.

The clinical implications of these findings for humans are unclear. Researchers speculate that bexarotene’s metabolism may change with longer exposure. The treatment regimen or administration interval may hold the key to success in the future. ReXceptor Therapeutics announced plans to attempt to “repurpose” bexarotene for use in treating AD. The company stated that it intends to launch a preliminary trial in humans to determine whether the drug crosses the human blood—brain barrier and clears amyloid. If so, subsequent human clinical trials to determine actual effectiveness could follow.

Transgenic mouse experiments in AD have been notably unreliable in the past, mainly because transgenic mice do not develop a disease identical to AD in humans. Unlike humans with the condition, for example, mice do not accumulate tau protein.

While patients and families certainly have the right to seek access to promising and experimental treatments, health care providers need to be able to present the promise of these treatments in a realistic manner. An editorial by a trio of researchers from the National Institutes of Health published in the August 9, 2012, issue of the New England Journal of Medicine, highlights some of the dilemmas health care practitioners face when startling results such as these regarding terminal, untreatable diseases are reported. The authors suggest that the results from the mouse model involving bexarotene are too preliminary to generate more than the most cautious optimism.

Experimental treatment with bexarotene is already FDA-approved for refractory cutaneous T-cell lymphoma, and the drug is available for off-label use. However, bexarotene’s potential risks in cancer patients include lipid abnormalities, acute pancreatitis, elevated liver function values, hypothyroidism, leukopenia, and altered response to insulin in diabetes. Adverse event profiles in patient populations other than cancer patients may differ, and bexarotene’s effect in human AD patients is unknown. While there is hope, more research is needed before any prescriber can ethically prescribe bexarotene for human AD patients.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.