Drugs for diabetes, inflammation, alcoholism — and even for treating
arthritis in dogs — can also kill cancer cells in the lab, according to a study
by scientists at the Broad Institute of MIT and Harvard and Dana-Farber Cancer
Institute. The researchers systematically analyzed thousands of already
developed drug compounds and found nearly 50 that have previously unrecognized
anti-cancer activity. The surprising findings, which also revealed novel drug
mechanisms and targets, suggest a possible way to accelerate the development of
new cancer drugs or repurpose existing drugs to treat cancer.
“We thought we’d
be lucky if we found even a single compound with anti-cancer properties, but we
were surprised to find so many,” said Todd Golub, chief scientific officer and
director of the Cancer Program at the Broad, Charles A. Dana Investigator in
Human Cancer Genetics at Dana-Farber, and professor of pediatrics at Harvard
Medical School.
The new work appears in the journal Nature Cancer. It is the largest
study yet to employ the Broad’s Drug Repurposing Hub, a collection that
currently comprises more than 6,000 existing drugs and compounds that are
either FDA-approved or have been proven safe in clinical trials (at the time of
the study, the Hub contained 4,518 drugs). The study also marks the first time
researchers screened the entire collection of mostly non-cancer drugs for their
anti-cancer capabilities.
Historically,
scientists have stumbled upon new uses for a few existing medicines, such as
the discovery of aspirin’s cardiovascular benefits. “We created the repurposing
hub to enable researchers to make these kinds of serendipitous discoveries in a
more deliberate way,” said study first author Steven Corsello, an oncologist at
Dana-Farber, a member of the Golub lab, and founder of the Drug Repurposing
Hub.
The researchers
tested all the compounds in the Drug Repurposing Hub on 578 human cancer cell
lines from the Broad’s Cancer Cell Line Encyclopedia (CCLE). Using a molecular
barcoding method known as PRISM, which was developed in the Golub lab, the
researchers tagged each cell line with a DNA barcode, allowing them to pool
several cell lines together in each dish and more quickly conduct a larger experiment.
The team then exposed each pool of barcoded cells to a single compound from the
repurposing library, and measured the survival rate of the cancer cells.
They found
nearly 50 non-cancer drugs — including those initially developed to lower
cholesterol or reduce inflammation — that killed some cancer cells while
leaving others alone.
Some of the
compounds killed cancer cells in unexpected ways. “Most existing cancer drugs
work by blocking proteins, but we’re finding that compounds can act through other
mechanisms,” said Corsello. Some of the four-dozen drugs he and his colleagues
identified appear to act not by inhibiting a protein but by activating a
protein or stabilizing a protein-protein interaction. For example, the team
found that nearly a dozen non-oncology drugs killed cancer cells that express a
protein called PDE3A by stabilizing the interaction between PDE3A and another
protein called SLFN12 — a previously unknown mechanism for some of these drugs.
These unexpected
drug mechanisms were easier to find using the study’s cell-based approach,
which measures cell survival, than through traditional non-cell-based
high-throughput screening methods, Corsello said.
Most of the
non-oncology drugs that killed cancer cells in the study did so by interacting
with a previously unrecognized molecular target. For example, the
anti-inflammatory drug tepoxalin, originally developed for use in people but
approved for treating osteoarthritis in dogs, killed cancer cells by hitting an
unknown target in cells that overexpress the protein MDR1, which commonly
drives resistance to chemotherapy drugs.
The researchers
were also able to predict whether certain drugs could kill each cell line by
looking at the cell line’s genomic features, such as mutations and methylation
levels, which were included in the CCLE database. This suggests that these
features could one day be used as biomarkers to identify patients who will most
likely benefit from certain drugs. For example, the alcohol dependence drug
disulfiram (Antabuse) killed cell lines carrying mutations that cause depletion
of metallothionein proteins. Compounds containing vanadium, originally
developed to treat diabetes, killed cancer cells that expressed the sulfate
transporter SLC26A2.
“The genomic
features gave us some initial hypotheses about how the drugs could be acting,
which we can then take back to study in the lab,” said Corsello. “Our
understanding of how these drugs kill cancer cells gives us a starting point
for developing new therapies.”
The researchers hope to study the repurposing library compounds in more
cancer cell lines and to grow the hub to include even more compounds that have
been tested in humans. The team will also continue to analyze the trove of data
from this study, which have been shared openly (https://depmap.org) with the
scientific community, to better understand what’s driving the compounds’
selective activity.
“This is a great
initial dataset, but certainly there will be a great benefit to expanding this
approach in the future,” said Corsello.
Journal article: https://www.nature.com/articles/s43018-019-0018-6
Source: https://myfusimotors.com/2020/01/26/dozens-of-non-oncology-drugs-can-kill-cancer-cells/
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