(Republica, Pixabay)
21 Jan. 2020. A systematic high-speed screen of more than 4,500 drugs on hundreds of cancer cell lines finds 49 approved drugs for a range of diseases are also able to treat cancer. A team from the Broad Institute, a genetics research center affiliated with Harvard University and MIT, and Dana-Farber Cancer Institute in Boston describe their process and findings in yesterday’s issue of the journal Nature Cancer.
Researchers from the two institutes led by Todd Golub, Broad’s chief scientist and director of its cancer program, are seeking more comprehensive and systematic methods to find drugs already approved for other diseases that are also active against cancer cells. Current drugs on the market are already tested for safety, which means in many cases, they need only later-stage clinical trials that test repurposed drugs for efficacy, short-cutting a time-consuming development process. But finding these extra capabilities is up to now, a hit-or-miss process, usually discovered more by accident than with deliberate methods.
In recent years, Broad Institute established a number of resources that make possible more systematic screening of current drugs for their cancer-fighting potential. One of those components is its Drug Repurposing Hub, a library with 4,518 approved drugs at the time of the study that today has 6,125 unique compounds. Another resource is Broad’s Cancer Cell Encyclopedia, a collection of cancer cells, and for this study produced 578 separate cancer cell lines with which to test the 4,518 drugs.
A third element, molecular bar coding, makes it possible to lab test thousands of drug compounds against hundreds of cancer cell lines in a reasonable amount of time. Molecular bar codes, also known as DNA bar codes, are predefined sequences of nucleic acids that can be added as tags with unique identifiers to chemical compounds or cells, much like printed bar codes on stickers applied to retail store goods or manufactured items in factories. Golub’s lab at Broad Institute developed Prism — short for Profiling relative inhibition simultaneously in mixtures — a technique that allows for simultaneous testing of multiple drugs against a target cell line, since each drug is uniquely identified with molecular bar codes.
The Prism screening returned 49 compounds with at least some activity against cancer cell targets, a number that surprised the researchers. “We thought we’d be lucky if we found even a single compound with anti-cancer properties,” says Golub in a joint statement, “but we were surprised to find so many.”
The screens revealed some drug compounds acted in different ways against cancer cells than many current cancer drugs. “Most existing cancer drugs work by blocking proteins,” says first author and Dana-Farber physician Steven Corsello, “but we’re finding that compounds can act through other mechanisms.” Of the 49 current drugs found with anti-cancer activity, for example, 11 show they stabilize interactions between two proteins, phosphodiesterase 3A or PDE3A and schlafen family member 12 or SLFN12, removing a barrier to enable the drugs to kill cancer cells.
Another surprise mechanism was the finding that tepoxalin, a drug originally developed for humans and now approved to treat arthritic inflammation in dogs, blocks the protein MDR1, which stands for multidrug resistance. In this case, MDR1 proteins drive resistance to cancer chemotherapy drugs. Other drugs treating alcohol dependence and diabetes were also found to be active against certain cancer cells.
The team says identifying repurposed drugs is just a first step, and in many cases they need to understand the drugs’ precise mechanisms against cancer cells. But these mechanisms can lead to new treatments as well. “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,” adds Corsello. “Our understanding of how these drugs kill cancer cells gives us a starting point for developing new therapies.”
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