Source: Susanna Hamilton/Broad Communications

Drugs that are currently used to treat a wide range of conditions such as diabetes, inflammation, alcoholism, and even canine arthritis, can also kill laboratory-grown cancer cells, according to the results of a study by scientists at the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute. Using a molecular barcoding technology called PRISM (profiling relative inhibition simultaneously in mixtures) the researchers were able to screen thousands of existing drug compounds against different types of cancer cell lines. The results identified 49 compounds with previously unrecognized anticancer activity. The researchers say their surprising findings, which highlighted novel anticancer mechanisms and targets, could feasibly be used to springboard the development of new anticancer drugs, or potentially even directly repurpose existing drugs for cancer therapy.

We thought we’d be lucky if we found even a single compound with anticancer properties,but we were surprised to find so many,” said Todd Golub, MD, CSO and director of the cancer program at the Broad, the Charles A. Dana investigator in human cancer genetics at Dana-Farber, and professor of pediatrics at Harvard Medical School. Golub and colleagues reported their findings in Nature Cancer, in a paper titled, “Discovering the anticancer potential of non-oncology drugs by systematic viability profiling.”

What if we could take thousands of drugs already approved to safely treat disease, as well as other compounds that have been studied as potential drugs, and find new uses for these old medicines? [Scott Sassone, Broad Institute]

The concept of repurposing existing marketed drugs for new clinical indications is “alluring,” the authors wrote. Drugs that have already been shown safe in humans could feasibly progress rapidly to clinical trials. And in principle, existing drugs with newly identified anticancer activity could represent the starting point for drug development, when new targets are discovered. However, the team continued, identifying anticancer activity in existing drugs has so far been largely a matter of chance. “To date, most oncology repurposing discoveries have been serendipitous … The ideal study would involve screening many drugs (most of which are non-oncology drugs) across a large panel of genomically characterized cell lines to capture the molecular diversity of human cancer.”

The team has developed the Broad’s Drug Repurposing Hub, a drug compound collection that at the time of the reported study contained 4,518 drugs, but has now grown to more than 6,000 existing drugs and compounds that are 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 study first author Steven Corsello, PhD, an oncologist at Dana-Farber, a member of the Golub lab, and founder of the Drug Repurposing Hub.

The team’s newly published study marks the first time that the entire collection of mostly noncancer drugs has been screened for anticancer activity. By using the PRISM molecular barcoding technology, which was developed in the Golub lab, the researchers were able to test all the compounds in the Drug Repurposing Hub on 578 human cancer cell lines from the Broad’s Cancer Cell Line Encyclopedia (CCLE). Each cell line was tagged with a DNA barcode, which allowed them to pool several cell lines together, which made it possible to conduct a much larger overall 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. “Cancer cell lines are labeled with unique DNA sequences, thereby allowing barcoded cell lines to be pooled with relative barcode abundance serving as a surrogate for cellular viability,” they wrote.

The screen identified 49 noncancer drugs that were active against some types of cancer cells, a number of which killed the 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 drugs with anticancer activity appeared to act not by activating, rather than inhibiting a protein, or by stabilizing a protein-protein interaction. These unexpected drug mechanisms were easier to find using the cell-based approach that measures cell survival, than through traditional non-cell-based high-throughput screening methods, Corsello said.

For example, the team found that nearly a dozen non-oncology drugs killed cancer cells that express PDE3A, by stabilizing the interaction between PDE3A and another protein called SLFN12. This represents a previously unknown mechanism of action for some of these drugs, and could help researches develop new types of anticancer drugs. “Compounds with remarkable chemical diversity kill PDE3A high-expressing cancer cell lines,” the investigators wrote. “A structural understanding of the interaction of these diverse compounds with PDE3A will probably inform future optimization of PDE3A–SLFN12-directed cancer therapeutics.”

Most of the noncancer drugs that showed anticancer activity interacted with a previously unrecognized molecular target. For example, the anti-inflammatory drug tepoxalin, which was originally developed for use in people but was approved for treating osteoarthritis in dogs, killed cancer cells through activity at an unknown target in cells that overexpress the protein MDR1, which commonly drives resistance to chemotherapy drugs. The screening results also indicated that the alcohol dependence drug disulfiram (Antabuse), killed cell lines carrying mutations that cause depletion of metallothionein proteins. Compounds containing vanadium, which were originally developed to treat diabetes, killed cancer cells that expressed the sulfate transporter SLC26A2. “Our finding that vanadium-containing compounds selectively kill cancer cells expressing high levels of the sulfate transporter SLC26A2 was also surprising, given that a mechanistic link between the two had not been previously,” the scientists noted.

The authors were also able to predict which drugs would be able to kill specific cancer cell lines, by looking at the cell’s genomic features, such as mutations and methylation levels, which were included in the CCLE database. They suggest that these genomic features could represent biomarkers to identify which patients would be most likely to 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 Corsello. “Our understanding of how these drugs kill cancer cells gives us a starting point for developing new therapies.”

Moving forward, the researchers hope to study the repurposing library compounds in additional cancer cell lines and to grow the hub to include even more compounds that have been tested in humans. “The PRISM Repurposing dataset described in this study represents nearly half of all drugs ever tested in humans,” they commented. “Given the large number of unexpected findings that emerged from this initial screen, we believe that expansion of the PRISM resource in both the dimension of drugs and cancer models is warranted.”

The investigators will also continue to analyze the data from their reported study, which have been made freely available to the scientific community——to better understand the mechanisms underpinning compound selectivity against certain cancer types. “This is a great initial dataset, but certainly there will be a great benefit to expanding this approach in the future,” said Corsello.

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