Potential Alzheimer’s Treatment from Existing Cancer Drugs

Two drugs previously approved by the FDA for cancer treatment might be instrumental in reversing Alzheimer’s disease, according to specialists. Researchers from the University of California, San Francisco (UCSF) suggest that letrozole, which is used for breast cancer, alongside irinotecan, a chemotherapy drug for lung and colon cancers, could potentially reverse brain damage associated with this neurodegenerative condition.

In their animal study, the UCSF team observed reductions in brain degeneration among mice treated with these cancer drugs, alongside noticeable improvements in their memory and learning abilities.

Alzheimer’s disease, a prevalent form of dementia, predominantly affects individuals over 65. Currently, around 7 million Americans are living with this condition, which leads to the death of more than 100,000 people each year.

The disease stems from the accumulation of toxic proteins—amyloid and tau—that disrupt cellular health in the brain, particularly affecting memory and cognitive functions.

Amyloid proteins tend to form clumps or plaques within brain cells, while tau proteins entangle into strands called tangles. At present, there are no definitive cures for Alzheimer’s, and only two therapies, Lecanemab (Leqembi) and Donanemab (Kisunla), are approved for early-stage treatment.

However, given that letrozole and irinotecan are already recognized for other uses, this might expedite the clinical trials needed for their application in treating Alzheimer’s.

Dr. Marina Sirota, a co-senior author and professor at UCSF, remarked on the complexities of Alzheimer’s and how their computational tools might facilitate a direct approach to the disease. “We’re excited that our computational approach led us to a potential combination therapy for Alzheimer’s based on existing FDA-approved medications,” she mentioned.

In patients with Alzheimer’s, the plaques and tangles hinder the transmission of electrical and chemical signals between neurons. Over time, this disruption can lead to significant brain damage, impacting a patient’s ability to communicate, care for themselves, and engage with their environment.

While the exact factors initiating the brain damage related to Alzheimer’s are still being explored, age and genetics are acknowledged risk factors. Lifestyle choices, such as lack of physical activity and high blood pressure, may also contribute to the disorder’s development.

Despite extensive research efforts, the road to effective dementia treatment is fraught with difficulties—recent statistics show a staggering 98 percent failure rate in drug development over the past few decades. Dr. Yadong Huang, a co-author and neurology professor at UCSF, explained that Alzheimer’s involves numerous genetic and protein alterations, complicating drug development that typically targets single genes or proteins.

Nonetheless, the UCSF researchers believe their findings might help mitigate or reverse the cognitive decline associated with Alzheimer’s.

The research team meticulously investigated how dementia affects gene expression in the brain, sifting through a database of over 1,300 drugs—antipsychotics, antibiotics, antifungals, and anti-cancer medications—to identify possible candidates for repurposing. They hoped to find drugs that could target the negative changes in neurons and supportive glial cells linked to Alzheimer’s.

Eventually, they identified letrozole and irinotecan as promising candidates for lowering Alzheimer’s risk. The combination treatment could effectively target various brain cells impacted by the disease, with letrozole possibly counteracting Alzheimer’s effects on neurons while irinotecan might aid in reversing damage to glial cells.

In tests on mice, the combination of these drugs significantly reduced harmful tau protein clumps and enhanced learning and memory tasks. Yet, the mechanisms by which these cancer drugs reverse damage remain elusive.

Researchers speculate that letrozole may inhibit estrogen production, a hormone that influences many genes, which in turn could lessen the genetic risk of developing Alzheimer’s. Additionally, irinotecan might help in managing inflammation by preventing rapid cell reproduction and DNA damage in glial cells.

Given that this was an animal study, the team is eager to proceed with clinical trials involving human patients with Alzheimer’s.

Dr. Huang emphasized the more favorable timeline and cost for repurposing existing drugs compared to developing new ones, which typically spans over a decade and can cost hundreds of millions. However, he underscored that a truly effective drug to slow cognitive decline has not yet emerged.

Despite their encouraging findings, there are risks associated with these drugs; for instance, letrozole can lead to hot flashes, while irinotecan may cause severe diarrhea. Both medications have potential side effects like nausea and vomiting.

Dr. Sirota cautioned that the side effects could complicate the treatment approach for Alzheimer’s patients, stating, “It’s not that it’s a slam dunk.”

The insights from this study are published in the journal Cell.