Study finds a combination of cancer drugs could treat Alzheimer’s

By Stephen Beech

Two cancer drugs could be combined to treat the most common form of dementia, suggests new research.

A study comparing the gene expression signature of Alzheimer's disease with those elicited by 1,300 approved drugs found a combination of two cancer medications that may treat the debilitating disorder.

American scientists have identified cancer drugs that promise to reverse the changes that occur in the brain during Alzheimer’s, potentially slowing or even reversing its symptoms.

The combination of drugs reduced brain degeneration in mice with Alzheimer’s - and even restored their ability to remember.

The study first analyzed how Alzheimer's disease altered gene expression in single cells in the human brain.

Researchers then looked for existing drugs that were already approved by the Food and Drug Administration (FDA) and cause the opposite changes to gene expression.

The team was looking specifically for drugs that would reverse the gene expression changes in neurons and in other types of brain cells called "glia" - all of which are damaged or altered in patients with Alzheimer’s.

The researchers analyzed millions of electronic medical records to show that patients who took some of the drugs as part of their treatment for other conditions were less likely to get Alzheimer’s disease.

When they tested a combination of the two top drugs — both of which are cancer medications — in a mouse model of Alzheimer’s, it reduced brain degeneration in the mice, and even restored their ability to remember.

Study co-senior author Dr. Marina Sirota, of the University of California, San Francisco (UCSF), said: “Alzheimer’s disease comes with complex changes to the brain, which has made it tough to study and treat, but our computational tools opened up the possibility of tackling the complexity directly.

“We’re excited that our computational approach led us to a potential combination therapy for Alzheimer's based on existing FDA-approved medications.”

Alzheimer’s causes a relentless decline in cognition, learning, and memory.

But decades of research have only produced two FDA-approved drugs, neither of which can meaningfully slow the decline.

Study co-senior author Dr. Yadong Huang, also of UCSF, said: "Alzheimer’s is likely the result of numerous alterations in many genes and proteins that, together, disrupt brain health.

"This makes it very challenging for drug development - which traditionally produces one drug for a single gene or protein that drives disease.”

The researchers took publicly available data from three studies of the Alzheimer’s brain that measured single-cell gene expression in brain cells from deceased donors with or without Alzheimer’s disease.

The team used the data to produce gene expression signatures for Alzheimer’s disease in neurons and glia.

They compared the signatures with those found in the Connectivity Map, a database of results from testing the effects of thousands of drugs on gene expression in human cells.

Out of 1,300 drugs, 86 reversed the Alzheimer’s disease gene expression signature in one cell type, and 25 reversed the signature in several cell types in the brain.

But just 10 had already been approved by the FDA for use in humans.

Looking through anonymized medical records of 1.4 million people over the age of 65, the team found that several of the drugs seemed to have reduced the risk of developing Alzheimer’s disease over time.

Study lead author Dr. Yaqiao Li said: “Thanks to all these existing data sources, we went from 1,300 drugs, to 86, to 10, to just five.

“In particular, the rich data collected by all the UC health centers pointed us straight to the most promising drugs. It's kind of like a mock clinical trial.”

The team chose two cancer drugs out of the top five drug candidates for lab testing.

They predicted one drug, letrozole, would remedy Alzheimer’s in neurons; and another, irinotecan, would help glia.

Letrozole is usually used to treat breast cancer; irinotecan is usually used to treat colon and lung cancer.

The team used a mouse model of aggressive Alzheimer’s disease with multiple disease-related mutations.

The findings, published in the journal Cell, showed that, as the mice aged, symptoms resembling Alzheimer’s emerged, and they were treated with one or both drugs.

The combination of the two cancer drugs reversed multiple aspects of Alzheimer’s in the mice.

It undid the gene expression signatures in neurons and glia that had emerged as the disease progressed.

It also reduced both the formation of toxic clumps of proteins and brain degeneration.

And it restored memory.

Dr. Huang said: "It’s so exciting to see the validation of the computational data in a widely used Alzheimer’s mouse model."

He expects the research to advance soon to a clinical trial so the team can directly test the combination therapy in Alzheimer’s patients.

Dr. Sirota added: “If completely independent data sources, such as single-cell expression data and clinical records, guide us to the same pathways and the same drugs, and then resolve Alzheimer’s in a genetic model, then maybe we're onto something.

“We’re hopeful this can be swiftly translated into a real solution for millions of patients with Alzheimer’s.”