As treatment options for Alzheimer’s disease remain limited, researchers are exploring the repurposing of cancer medications to address cognitive decline.
The incidence of Alzheimer’s is on the rise due to an aging global population, yet no cure currently exists. Efforts to discover new therapies that can halt the progression of the disease instead of merely managing symptoms have often been unsuccessful.
At present, only two medications, Leqembi and Kisunla, have received FDA approval to slow the progression of early Alzheimer’s disease, and the extent of their effectiveness is considered limited.
Several pharmaceutical firms have either shelved or discontinued their Alzheimer’s drug development initiatives after encountering trial failures. Others are investigating the potential of established medications, including popular weight loss drugs in combating the disease.
In this context, researchers at the University of California, San Francisco, conducted extensive screenings of existing drugs that could be repurposed for Alzheimer’s treatment, aiming to shorten the time required for patient access to these drugs. They analyzed a database of over 1,300 different medications, spanning various drug classes such as antipsychotics, antibiotics, antifungals, and chemotherapeutics, and assessed their impact on gene expression.
Their recent study, published in the journal Cell, pinpointed two cancer drugs as the leading candidates to potentially mitigate the risk of Alzheimer’s in patients. When used in combination, these drugs demonstrated the ability to slow or even reverse Alzheimer’s symptoms in mouse models. One of the medications is typically used for breast cancer treatment, while the other targets colon and lung cancers.
Significant alterations in gene expression in the brain are characteristic of Alzheimer’s disease, leading to the increased synthesis of certain proteins and decreased production of others. These disruptions can impair brain functionality and result in symptoms such as memory loss.
According to the researchers, the two drugs, identified from a database of nearly 90, were able to reverse the expression of genes associated with Alzheimer’s in human brain cells. Furthermore, based on electronic medical records, five specific drugs appeared to lower Alzheimer’s risk among actual patients, ultimately leading the authors to select two FDA-approved cancer treatments for animal testing.
“We were not anticipating that cancer medications would emerge as strong contenders,” remarked Marina Sirota, interim director of the UCSF Bakar Computational Health Sciences Institute.
The authors noted that letrozole, a breast cancer treatment, seems to modify gene expression within neurons, while irinotecan, a colon cancer medication, appears to influence gene expression in glial cells that support the nervous system. Alzheimer’s disease leads to nerve cell destruction, excess glial cell proliferation, and brain inflammation.
A 2020 study indicated that breast cancer patients treated with letrozole had a lower incidence of Alzheimer’s disease compared to those who did not receive the drug. Similarly, colorectal cancer survivors who were administered irinotecan exhibited a reduced risk of Alzheimer’s disease, as noted in research from 2021.
After evaluating the drugs in mice, the study authors discovered that the combination of the two medications reversed cognitive decline and enhanced memory in mice displaying traits of Alzheimer’s disease as they aged.
Given that results observed in mice do not always have a direct correlation with human outcomes, researchers aim to conduct clinical trials with Alzheimer’s patients.
“The development of new medications typically incurs costs in the millions, often billions, and can span over a decade. In contrast, repurposed medications may require only two to three years and carry significantly lower costs to reach clinical trial stages,” Sirota explained.
“Currently, we are not producing highly effective treatments that can significantly decelerate cognitive decline,” she added.
The challenge in developing Alzheimer’s treatments lies in the intricate nature of the disease, with its exact causes remaining largely elusive.
At this point, the authors admit that the precise mechanisms by which cancer drugs may be effective against Alzheimer’s are uncertain. One hypothesis suggests that breast cancer medications inhibit estrogen production—a hormone that regulates the expression of numerous genes. Colon cancer drugs might mitigate brain inflammation by preventing glial cell proliferation, yet Huang notes that there could be additional explanations.
Dr. Melanie McReynolds, a biochemistry assistant professor at Penn State University who was not involved in the research, offered another perspective.
She suggested that the study indicates various cancer drugs may prove beneficial in treating Alzheimer’s by modulating glucose metabolism, the process by which cells generate energy. McReynolds emphasized that this process is vital for communication among different brain cells.
“Aging, stress, and illness can disrupt that communication,” she stated.
McReynolds expressed that the drug combinations evaluated in the current research have the potential to reverse metabolic declines.
However, it is crucial to understand how Alzheimer’s patients will respond to these cancer drug combinations. Letrozole can induce hot flashes, while irinotecan is known for causing severe diarrhea. Both treatments may also lead to nausea and vomiting.
“These medications come with significant side effects, so it’s essential to weigh these risks carefully and determine whether such side effects are manageable for individuals with Alzheimer’s,” stated Sirota. “It’s not a straightforward solution.”
