It turns out that certain approved, safe drugs have unexpected properties against cancer.
Scientists occasionally find that a medication designed for treating one disorder has unexpected utility in treating another.
A well-known case in point is pain relief aspirin, which turns out to be effective in cardiovascular disease prevention.
With that in mind, researchers took a fresh look at thousands of drug compounds to find out if anyone would kill cancer cells without destroying healthy cells.
The investigation concludes that almost 50 approved drug compounds have previously unrecognized abilities to fight cancer.
“We thought we would be lucky if we even found 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, Cambridge, MA, and Cancer Program Director of the Institute.
He is the study’s senior researcher, summed up in the journal Nature Cancer.
The study was a partnership between Broad Institute researchers, which is a joint entity of Massachusetts Institute of Technology and Harvard University, and the Boston-based Dana-Farber Cancer Institute.
A drug repurposing database
The Drug Repurposing Hub at Broad Institute is a huge database designed to help researchers find new applications for drugs already licensed.
The study’s first author, Dr. Steven Corsello, the hub founder and oncologist at Dana-Farber, says, “We developed the repurposing hub to allow researchers to make these kinds of serendipitous discoveries in a more deliberate way.”
New research from the team marks the first time the hub has been used to identify unintended anticancer compounds.
The researchers tested 4,518 drugs— which at the time comprised the database— from the Broad Institute’s Cancer Cell Line Encyclopaedia on 578 human cancer cell lines. Since that time the hub has grown to include over 6,000 compounds.
The researchers tagged each cell line with a DNA barcode using a molecular method called PRISM developed by Dr. Golub’s lab to effectively search for combinations. Dr Golub is also a medical school professor at Harvard.
The barcodes accelerated the testing by allowing the researchers to pool multiple cell lines into a single dish without losing the ability to track each one’s survival rate as it reacted to a drug compound.
New mechanisms revealed
The ways in which some compounds have attacked the cancer cells have been shocking, exposing previously unknown cancer vulnerabilities.
Most of those mechanisms involved interacting in cancer cells with previously overlooked molecular targets.
Dr. Corsello explains, “The majority of existing cancer drugs work by blocking proteins, but we find that compounds can act by other mechanisms.”
For example, some of the drugs did not inhibit proteins in cancer cells as expected, but instead fought cancer by activating other proteins or stabilizing protein interactions.
Tepoxalin, an anti-inflammatory agent, interacted with an unknown target to suppress the expression of a protein that would otherwise improve the chemotherapy resistance of cancer cells.
The drug was originally intended for human use but is currently approved for dogs to treat osteoarthritis.
The cell-based approach of the analysis has been able to expose such unexpected interactions more readily than other methods of testing.
The researchers found that medications developed to treat diabetes, reduce inflammation and control alcohol use disorder were among those that had potential uses in cancer treatment.
Making predictions
Finally, the thorough listing of the mechanisms by which each line of cancer cells functions by the cell line encyclopedia allowed the team to predict which compounds could most effectively combat the lines.
For instance, disulfiram– also known as Antabuse, a drug that can promote substance use disorder recovery– targeted cell lines with mutations that depleted specific proteins called metallothioneins.
One hope is that the cancer-causing mechanisms of each cell line will serve as biomarkers in the future, and that researchers can decide which drugs are particularly good for 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
