Researchers in Boston might have hit a gold mine when it comes to cancer treatment—instead of creating new chemical compounds to treat cancer cells, they have taken thousands of pre-existing drug compounds designed to treat other illnesses and screened them for their effects on cancer. Nearly 50 of these medications were found to kill cancer cells.
The aim of this study was to create a public repository of knowledge on the subject, as over 4,000 drugs were tested, in a joint project of Harvard, MIT, and the Dana-Farber Cancer Institute. Together, they formed the PRISM drug repurposing resource. The drugs tested in the study spanned a wide variety, including medication designed to treat diabetes, inflammation, alcohol abuse, and even arthritis in dogs.
Scientists reported their findings contained an “unexpectedly high rate of anti-cancer activity” – this massive screening strategy tested 4,518 drugs against 578 laboratory cancer cell lines spanning 24 tumor types, and identified 49 non-cancer drugs that selectively killed cancer cells and whose activity against cancer could be predicted using molecular biomarkers. Another 103 compounds reporting less selectivity against certain cancer cell lines were also identified.
While the results have only been seen in laboratory studies so far, many drugs might soon be tested in clinical trials for cancer, or perhaps used as a starting point for researchers to make a more potent version of the original drug, specifically designed to destroy cancer cells.
“It is conceivable that some non-oncology drugs could be brought directly to clinical trials for testing in cancer patients,” said the study authors. “However, it is likely that the potential drug candidates will require further study and modification before being introduced into clinical studies.”
“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, M.D., an author on the study with Steven Corsello.
This work builds on the previous work of Broad’s Drug Repurposing Hub, a collection that currently comprises more than 6,000 existing drugs and compounds that are either FDA-approved or have been proven safe in clinical trials (at the time of the study, the Hub contained 4,518 drugs). This new study also marks the first time researchers screened the entire collection of mostly non-cancer drugs for their anti-cancer capabilities.
It was notable that some of the compounds killed cancer cells in unexpected ways. “Most existing cancer drugs work by blocking proteins, but we’re finding that [these] compounds can act through other mechanisms,” said Corsello.
Some of the drugs Corsello and colleagues identified appear to kill or stop cancer cells not by inhibiting a protein, but by activating a protein or stabilizing a protein-protein interaction. For example, the team found that nearly a dozen non-oncology drugs killed cancer cells which expressed a protein called PDE3A by stabilizing the interaction between PDE3A and another protein called SLFN12 — a previously unknown mechanism for some of these drugs.
Most of the non-oncology drugs that killed cancer cells in the study did so by interacting with a previously unrecognized molecular target. For example, the anti-inflammatory drug tepoxalin, originally developed for use in people but approved for treating osteoarthritis in dogs, killed cancer cells by hitting an unknown target in cells that overexpress the protein MDR1, which commonly drives resistance to chemotherapy drugs.
Furthermore, the researchers on this study were able to predict whether certain drugs could kill each cell line by looking at the cell line’s genomic features, such as mutations and methylation levels, which were included in the CCLE database. This suggests that these features could one day be used as biomarkers to identify patients who will most likely benefit from certain drugs.
For example, the alcohol dependence drug disulfiram (Antabuse) killed cell lines carrying mutations that cause depletion of metallothionein proteins. Compounds containing vanadium, originally developed to treat diabetes, killed cancer cells that expressed the sulfate transporter SLC26A2.
The observations made in this study may represent starting points for new drug development. “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 novel idea of exploring how cancer cells react to drugs instead of developing drugs based on our limited understanding of cancer works has given scientists more information to work with and the potential to develop cancer drugs that are more precise and effective. Hopefully, the drugs in this study that go on to clinical trials will be found to be effective.