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Uncovering New Tricks for Old Drugs

Scientists from Broad Institute of MIT and Harvard and Dana-Farber Cancer institute screen drug compounds that have previously unrecognized anti-cancer activity.

Currently available drugs for diabetes, inflammation, alcoholism – and even for treating arthritis in dogs – may have the potential to have anti-cancer abilities. Researchers systematically analysed thousands of already developed drug compounds and have found nearly 50 that have previously unrecognized anti-cancer activity.

These findings also revealed novel drug mechanisms and targets suggesting a possibility to accelerate the development of new cancer drugs or repurposing of existing drugs to treat cancers.

“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 Todd Golub, chief scientific officer and director of the Cancer Program at the Broad, Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber, and professor of paediatrics at Harvard Medical School.

The study published on Nature Cancer, marks the first time researchers screened an entire collection of mostly non-cancer drugs for anti-cancer capabilities. As the largest study to presently employ the Broad’s Drug Repurposing Hub, the researchers tested all the compounds on 578 human cancer cell lines from Broad’s Cancer Cell Line Encyclopaedia (CCLE).

Using a molecular barcoding method known as PRISM, developed in the Golub lab, the team labelled each cell line with a DNA barcode, allowing them to pool several cell lines together in each dish and with reduced time. The pool of barcoded cells were then exposed to a single compound from the repurposing library, and the survival rate of cancer cells were measured.

Historically, scientists have stumbled upon new uses for a few existing medicines, such as the discovery of aspirin’s cardiovascular benefits. “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, an oncologist at Dana-Farber, a member of the Golub lab, and founder of the Drug Repurposing Hub.

They found nearly 50 non-cancer drugs — including those initially developed to lower cholesterol or reduce inflammation — that killed some cancer cells while leaving others alone.

Some of the four-dozen drugs that were screened found to act by activating a protein or stabilizing a protein-protein interaction. Most of the non-oncology drugs that killed cancer cells in the study did so by interacting with a previously unrecognized molecular target.

Analysing the cell line’s genomic features, such as mutations and methylation levels researchers were able to predict whether certain drugs could kill each cell line. These were included in the CCLE database. The finding suggests that these features could be used as biomarkers to identify patients who most likely will 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.”

The team will continue to study the data which is also shared openly with the scientific community. The researchers will further analyse the repurposing library compounds in more cancer cell lines and to grow 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 Corsello. [APBN]