It turns out some approved, safe drugs have unexpected anticancer properties.
Occasionally, researchers find that a drug developed to treat one condition has unexpected value in treating another.
A well-known case in point is the pain reliever aspirin, which turns out to be of use in preventing cardiovascular disease.
With that in mind, researchers have taken a fresh look at thousands of drug compounds to discover whether any could kill cancer cells without harming healthy cells.
The investigation concludes that nearly 50 approved drug compounds have previously unrecognized cancer-fighting capabilities.
“We thought we’d be lucky if we found even a single compound with anticancer properties, but we were surprised to find so many,” says Dr. Todd Golub, chief scientific officer at the Broad Institute, in Cambridge, MA, and director of the institute’s cancer program.
He is the senior investigator of the study, which is summarized in the journal
The study was a collaboration between researchers from the Broad Institute, which is a joint body of the Massachusetts Institute of Technology and Harvard University, and the Dana-Farber Cancer Institute, in Boston.
The Broad Institute’s Drug Repurposing Hub is a massive database designed to help researchers find new uses for already approved compounds.
The first author of the study, Dr. Steven Corsello, the founder of the hub and an oncologist at Dana-Farber, says, “We created the repurposing hub to enable researchers to make these kinds of serendipitous discoveries in a more deliberate way.”
The team’s new research marks the first time the hub has been used to find compounds with unintended anticancer value.
The researchers tested 4,518 drugs — which, at the time, comprised the database — on 578 human cancer cell lines from the Broad Institute’s Cancer Cell Line Encyclopedia. The hub has since grown to include more than 6,000 compounds.
To search for combinations effectively, the researchers tagged each cell line with a DNA barcode using a molecular method called PRISM that Dr. Golub’s lab had developed. Dr. Golub is also a professor at Harvard Medical School.
The barcodes sped up the testing by allowing the researchers to pool several cell lines in a single dish without losing the ability to track the survival rate of each as it reacted to a drug compound.
The ways in which some compounds fought the cancer cells were surprising, revealing previously unknown vulnerabilities in cancer.
Most of these mechanisms involved interacting with previously overlooked molecular targets in the cancer cells.
Dr. Corsello explains, “Most existing cancer drugs work by blocking proteins, but we’re finding that compounds can act through other mechanisms.”
For example, some of the drugs did not inhibit proteins in cancer cells as expected, but instead fought the cancer by activating other proteins or stabilizing interactions between proteins.
Tepoxalin, an anti-inflammatory compound, interacted with an unknown target to weaken the expression of a protein that otherwise strengthens cancer cells’ chemotherapy resistance.
This compound was originally intended for use in humans but is currently approved for treating osteoarthritis in dogs.
The study’s cell-based approach was able to expose these surprising interactions more readily than other research methods.
Finally, the cell line encyclopedia’s comprehensive listing of the mechanisms by which each cancer cell line operates enabled the team to predict which compounds could combat the lines most effectively.
For example, disulfiram — also known as Antabuse, a drug that can support the treatment of alcohol use disorder — attacked cell lines with mutations that depleted specific proteins called metallothioneins.
One hope is that, going forward, each cell line’s cancer-causing mechanisms can serve as biomarkers, and that researchers will determine which drugs are especially good at targeting them.
“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. Our understanding of how these drugs kill cancer cells gives us a starting point for developing new therapies.”
– Dr. Steven Corsello