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“The study highlights the potential power and importance of this type of approach,” says Alexis Borisy, an entrepreneur in residence at Third Rock Ventures in Boston. “In a short period of time, we’ve gone from the discovery of the mutation to the design of a drug that is selective for that mutation, and which leads to dramatic clinical effects.” Borisy is the CEO of a startup, Foundation Medicine, that’s developing genetic screening tools to match cancer patients with the most appropriate drugs.

The new drug candidate does have limitations. Many patients develop resistance anywhere from three months to two years after beginning treatment, a problem that has occurred with other targeted cancer therapies as well. Scientists hope to overcome this problem by combining the drug with other compounds, an approach that worked with Gleevec, a targeted cancer drug used to treat some kinds of leukemia.

“We know some other genetic alterations that accompany BRAF, so the strategy would be to try to target more than one,” says Flaherty. “It’s like HIV, where doctors routinely use multiple drugs.” One such study, combining a BRAF inhibitor with a second drug that targets another protein in the same molecular pathway, has already begun. Researchers also aim to find the genetic variations that lead to resistance, which could ultimately help direct the most effective combinations.

The benefits of BRAF inhibitors are likely to extend beyond melanoma; the mutation is found in approximately 7 to 8 percent of all cancers, and tests of the drug in colorectal cancer are now underway. Scientists hope that studies such as these will lead to a new way to define cancer, relying on molecular characteristics rather than the tissue of origin.

A number of other clinical studies are underway for drugs targeting other mutations involved in various types of cancers. However, most of these mutations are much less frequent than BRAF. “A fundamental question that remains in the field is how many more targets like BRAF will there be,” says Flaherty. “That’s still a matter of discovery.”

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Credit: Peter MacCallum Cancer Centre/Plexxikon

Tagged: Biomedicine, cancer, genetics, drugs, drug development, personal genomics, genetic mutations

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