Even after the complicated task of drug development, pharmaceuticals have to be rigorously tested before they can be offered to patients, so it can be much easier to find more than one application for an existing medication. Scientists have now tested a wide variety of drugs that are used to treat many different conditions to see if they had any anti-cancer effect. They were surprised to find that nearly fifty of the ones they assessed, including drugs for alcoholism, diabetes, inflammation, and pet medication for arthritis, exhibited anti-cancer activity that was previously unknown. The work has been reported in Nature 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 Professor Todd Golub, chief scientific officer and director of the Cancer Program at the Broad Institute of MIT and Harvard, and Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber.
This work utilized a collection of around 6,000 drugs that have either been proven to be safe in clinical trials or are approved by the Food and Drug Administration; it's called the Drug Repurposing Hub. The researchers tagged 578 human cancer cell lines with DNA barcodes so the vast number of cells could be pooled and exposed to the many medications. The survival rate of the various cancer cells was measured so the investigators could determine which of the drugs kill cancer.
"We created the repurposing hub to enable researchers to make these kinds of serendipitous discoveries in a more deliberate way," said the first author of the study Steven Corsello, an oncologist at Dana-Farber and founder of the Drug Repurposing Hub.
The researchers discovered the anti-cancer activity of fifty drugs, some of which killed selectively, while others destroyed cancer cells in surprising ways.
"Most existing cancer drugs work by blocking proteins, but we're finding that compounds can act through other mechanisms," said Corsello. Some of these drugs don't work by interfering with a protein; they stabilize a chemical interaction or activate a protein, for example. This cell-survival-based approach made identifying these mechanisms easier, said Corsello.
In another case, cancer cells were killed by drugs that interacting with something unknown. For example, tepoxalin is used to treat osteoarthritis in dogs, and this anti-inflammatory medication kills cancer after acting on an unknown target in cells that express high levels of a protein called MDR1.
Genetic characteristics like methylation levels and mutations in the cancer cell lines enabled the researchers to predict which drugs would kill them. For example, cells that carried mutations that reduced their metallothionein protein levels were killed by a drug for alcohol dependence, called Antabuse. If cells expressed a certain sulfate transporter called SLC26A2, they were susceptible to drugs that contain vanadium.
"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. This is a great initial dataset, but certainly, there will be a great benefit to expanding this approach in the future."
Sources: AAAS/Eurekalert! via Broad Institute of MIT and Harvard, Nature Cancer
