Nearly 50 existing non-cancer drugs may have previously unrecognized cancer-fighting properties, according to an extensive review of thousands of drug compounds by researchers from the Broad Institute—a joint body of the Massachusetts Institute of Technology and Harvard University—and the Dana-Farber Cancer Institute.
“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 senior author Todd Golub, MD, chief scientific officer and director of the Cancer Program at the Broad Institute, Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber, and professor of pediatrics at Harvard Medical School, Boston, MA.
Finding a new purpose
Sometimes, a drug indicated for the treatment of one condition may have unexpected efficacy in treating another. Aspirin, for example, is one such drug. This ubiquitous pain reliever isn’t only good for headaches—it can also prevent cardiovascular events. Even better: It’s already gone through the rigors of clinical safety testing and is FDA-approved. Discovering that an FDA-approved drug may have value for a second (or third) indication is like finding a diamond in the rough, given the high costs and time associated with new drug development.
This line of thought prompted Dr. Golub and colleagues to test 4,518 existing drugs—the majority of which (77%) were not oncology related—against 578 cancer cell lines. Their aim was to determine whether non-oncology agents have potential as future cancer therapeutics. These drugs were identified from the Broad Institute's Drug Repurposing Hub, a collection of existing drugs and compounds that were either FDA-approved or have been proven safe in clinical trials.
“We created the repurposing hub to enable researchers to make these kinds of serendipitous discoveries in a more deliberate way,” said lead author Steven Corsello, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, and the founder of the Broad Institute’s Drug Repurposing Hub.
Dr. Golub, Dr. Corsello, and fellow researchers tagged each cell line with a DNA barcode and pooled several cell lines together in each lab dish. This technique allowed the researchers to more quickly conduct a larger experiment. They then exposed each pool of barcoded cells to a single compound and tracked the survival rate of the cancer cells.
Some of the compounds demonstrated anti-cancer activity in surprising ways, demonstrating unknown vulnerabilities in cancer. For instance, some of the compounds fought cancer by activating proteins rather than inhibiting them.
“Most existing cancer drugs work by blocking proteins, but we’re finding that compounds can act through other mechanisms,” said Dr. Corsello.
The researchers found that drugs for diabetes, inflammation, and alcohol dependence were among those that had the greatest potential for cancer treatment.
By analyzing each cell line’s genomic features—including mutations and methylation levels—the researchers were able to predict whether certain drugs could kill the cell lines. For instance, disulfiram—a drug used for the treatment of alcohol dependence—killed cell lines with mutations that cause metallothionein protein depletion. In addition, vanadium-containing compounds, which are used to treat diabetes, killed cancer cells that expressed the sulfate transporter SLC26A2. Perhaps most interestingly, tepoxalin—an anti-inflammatory drug approved the treatment of osteoarthritis in dogs—demonstrated selective activity against cancer cells that overexpress MDR1, a protein that drives resistance to chemotherapy drugs through an unknown route.
Just the beginning
Dr. Golub, Dr. Corsello, and their colleagues are hopeful that analysis of these features may one day be used as biomarkers to help identify patients who will most likely benefit from certain drugs.
“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 Dr. Corsello. “Our understanding of how these drugs kill cancer cells gives us a starting point for developing new therapies.”
They also hope to further study the repurposing library compounds in more cancer cell lines and to enlarge the hub to include even more compounds that have been tested in humans.
“This is a great initial dataset, but certainly there will be a great benefit to expanding this approach in the future, ” said Dr. Corsello.
If the researchers’ findings are further validated, it could translate to faster, new treatment options for patients with cancer.