One compound, a plant-derivative called gedunin, was identified through a conventional screening method as interfering with the hormone androgen in prostate cancer cells, which is an important strategy in treating the disease. But the exact mechanism of how gedunin blocked the androgen signaling pathway wasn’t clear. When the scientists searched the Connectivity Map for compounds that had similar activity to gedunin, though, they found matches to compounds that inhibit heat shock proteins and thus suppress androgen receptor activity.
The other finding involved a specific type of leukemia that was resistant to traditional chemotherapy. A team led by Scott Armstrong, an assistant professor at Harvard Medical School and Children’s Hospital in Boston, determined the signature of the drug-resistant cells, queried the Connectivity Map, and found a match to sirolimus, a drug currently used to prevent rejection after organ transplantation. When they tested the drug in the lab, the scientists found that it re-sensitized the leukemia cells to chemotherapy, reversing the drug resistance.
“That was a particularly gratifying example for all of us,” Lamb says, “because sirolimus is already FDA-approved for another indication. That means that this compound is known to be safe and tolerated by humans, and the path to clinical evaluation of sirolimus can probably be tested in the clinic much more quickly.”
The team plans to expand the map to cover all 1,400 or so drugs approved by the FDA, an effort that should take between one and two years. “We wanted to make data that was broadly useful, so that requires a systematic approach to data generation,” Lamb says. “And then if you can make that database accessible to the world in a way which is easy for the world to interact with it, that would solve a lot of problems for a lot of people.”
The work done by the Broad scientists “is right on target,” says Gregory Riggins, associate professor of neurosurgery, oncology, and genetic medicine at Johns Hopkins University. “This kind of group effort and approach is therapeutic-directed and is what is needed from the research community.”