Research at Broad
Institute of MIT and Harvard and Dana-Farber Cancer Institute shows that many
non-oncology
drugs, including the drugs for diabetes, inflammation, alcoholism -- and
even for treating arthritis in dogs kill cancer cells in lab. The researchers 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.
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.
To explore more
interesting trends in cancer research, do join us at Paris, France, this July
1-2, 2020. For more info, PS: Cancer
Research 2020 | Brochure
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