Researchers Zero in on New Drug Combination Strategy

CAMBRIDGE, Mass. — Modern drug discovery hinges on the hunt for magic bullet molecules—single drug therapies that derail disease by attacking a specific cellular target. Despite the high profile success of drugs like Gleevec, which treats a form of leukemia by inhibiting the function of a single protein, the magic-bullet approach has fallen short in treating diseases caused by multiple cell defects or those affecting more than one type of cell, which is the majority of human ailments.

Doctors often rely instead on combination therapies, an approach that has proven successful in the treatment of cancer, infectious disease and neurological disorders. But new drug combinations typically are forged from chemical agents already known to be effective in treating a specific disease, a strategy that scientist Brent Stockwell says represents only a fraction of the combinations possible between currently approved drugs.

Stockwell’s team at Whitehead Institute for Biomedical Research, in collaboration with scientists at CombinatoRx Inc. in Boston, Mass., recently reported the development of the first systematic approach to the discovery of novel combination drugs. Their approach uses high-throughput screens to rapidly identify combinations of compounds that pair synergistically to produce a desired therapeutic effect.

Remarkably, the researchers identified several novel pairings with significant therapeutic promise, including a new combination that kills an infectious, drug-resistant strain of the yeast Candida albicans while leaving human cells unharmed.

“Clinical results tell us that multi-component therapeutics often are successful in treating complex diseases,” said Stockwell. “This method enables us to unlock an enormous set of potential therapeutic combinations that, left to traditional methodology, may have never been discovered.”

Results from this study were published recently in the journal Proceedings of the National Academy of Science.

In combination, two drugs may produce a result not at all similar to the activity of the individual components, much in the same way that two colors can be combined to form a third, distinct color (take yellow and blue, for instance, which combine to make green).

Scientists attribute this to the combined effect of both drugs on the complex signaling networks that coordinate activity within and between cells. When used in combination, drugs interrupt or act on these networks at multiple points, and affect the cell in ways that the individual components cannot.

For example, Stockwell and his colleagues discovered that a combination of an antipsychotic drug and an antiprotozoal (used to kill small, infectious organisms known as protozoa) suppressed tumor growth in mice, a feat neither can do alone.

Although the screening method cannot determine if a combination is an ideal fit for use in patients, it enables researchers to make more informed decisions about which drugs to advance into expensive clinical trials. The process ultimately streamlines the “match-making” phase of starting a new chemical relationship, delving directly into issues of real compatibility.

In the case of the antipsychotic and antiprotozoal combination, both of which are approved for human use, further studies are necessary to ensure that the drug combination produces no dangerous side effects. But without the new screen, this seemingly incongruent couple may never have been introduced.

In addition to producing new therapies, chemical combinations also may be used to study disease and reveal insight into the cellular pathways at their root.

“Our screening approach is complementary to other methods for exploring biological systems and protein networks and may be useful for studying the underlying biological pathways responsible for disease,” said Stockwell. “New drug combinations can be used as probes to study how changes in disease networks impact disease outcomes in model systems such as mice.”



Full citation

Borisy, A. A., Elliott, P. J., Hurst, N. W., Lee, M. S., Lehár, J., Price, E. R., ... & Keith, C. T. (2003). Systematic discovery of multicomponent therapeuticsProceedings of the National Academy of Sciences100(13), 7977-7982.



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