In a surprising twist, researchers used computational tools to find that two FDA-approved cancer drugs might counteract Alzheimer’s disease by reversing its gene expression patterns. After analyzing gene activity in Alzheimer’s-affected brain cells and comparing it with data from over 1,300 existing drugs, they discovered a powerful drug duo that not only reduced brain degeneration in mice but also restored memory. Credit: Stock
A study that compared
the gene expression profile of Alzheimer’s disease with
those triggered by 1,300 approved drugs identified a combination of two cancer
medications as a potential treatment for the most common form of dementia.
Researchers
from UC San Francisco and the Gladstone Institutes have discovered that certain
cancer medications may help counteract the brain changes caused by Alzheimer’s
disease. This breakthrough could lead to treatments that slow or potentially
reverse the condition’s symptoms.
To
begin, the scientists examined how Alzheimer’s alters gene activity in
individual brain cells. They then searched for FDA-approved drugs that produced
the opposite effect on gene expression.
Their
focus was on medications that could correct changes in neurons and glial cells,
both of which are disrupted during the progression of Alzheimer’s.
The
team also reviewed millions of anonymized medical records and found that people
who had taken some of these drugs for unrelated health issues were less likely
to develop Alzheimer’s.
Finally,
when the researchers tested the two most promising drugs (both originally
developed to treat cancer) in mice with Alzheimer’s-like symptoms, the results
were striking: the treatment reduced brain damage and helped restore memory function
in the animals.
“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,” said Marina Sirota, PhD, the interim
director of the UCSF Bakar Computational Health Sciences Institute, professor
of pediatrics, and co-senior author of the paper. “We’re excited that our
computational approach led us to a potential combination therapy for
Alzheimer’s based on existing FDA-approved medications.”
The
findings appeared in Cell on July 21. The research was funded in part
by the National Institutes of Health and
the National Science Foundation.
Big data from
patients and cells points to a new Alzheimer’s therapy
Alzheimer’s
disease affects 7 million people in the U.S. and causes a relentless decline in
cognition, learning, and memory. Yet decades of research have only produced two
FDA-approved drugs, neither of which can meaningfully slow this decline.
“Alzheimer’s
is likely the result of numerous alterations in many genes and proteins that,
together, disrupt brain health,” said Yadong Huang, MD, PhD, senior
investigator and director of the Center for Translational Advancement at
Gladstone, professor of neurology and pathology at UCSF, and co-senior author
of the paper. “This makes it very challenging for drug development — which
traditionally produces one drug for a single gene or protein that drives
disease.”
The
team 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. They used this data to produce gene
expression signatures for Alzheimer’s disease in neurons and glia.
The
researchers compared these 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.
Poring
through records housed in the UC Health Data Warehouse, which includes
anonymized health information on 1.4 million people over the age of 65, the
group found that several of these drugs seemed to have reduced the risk of
developing Alzheimer’s disease over time.
“Thanks
to all these existing data sources, we went from 1,300 drugs, to 86, to 10, to
just 5,” said Yaqiao Li, PhD, a former UCSF graduate student in Sirota’s lab
who is now a postdoctoral scholar in Huang’s lab at Gladstone and the lead author
of the paper. “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.”
A combination
therapy poised for primetime
Li,
Huang, and Sirota chose 2 cancer drugs out of the top 5 drug candidates for
laboratory 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. 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 animal model. It undid the gene
expression signatures in neurons and glia that had emerged as the disease
progressed. It reduced both the formation of toxic clumps of proteins and brain
degeneration. And, importantly, it restored memory.
“It’s
so exciting to see the validation of the computational data in a widely used
Alzheimer’s mouse model,” Huang said. He expects the research to advance soon
to a clinical trial so the team can directly test the combination therapy in
Alzheimer’s patients.
“nbs,
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,” Sirota said. “We’re
hopeful this can be swiftly translated into a real solution for millions of
patients with Alzheimer’s.”
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