Clues to a Cure May Reside in Glioblastoma's Genome
Date: June 1, 2009
Gregory Riggins believes it may already be out there—a drug that can extend the survival time of patients with a glioblastoma. There’s a good possibility, he says, that a drug approved for another purpose or one sitting on a shelf in a laboratory somewhere can destroy the cells that cause this most lethal of brain tumors. Riggins is committed to finding it.
“The idea,” says the director of Johns Hopkins’ Brain Cancer Biology and Therapy Research Laboratory, “is to make sure there’s not already something that we can use in humans before going to design a new drug, which can take 10 to 15 years and perhaps millions of dollars.”
Basically, Riggins is using what he calls a “brute force” approach. “We try to gather up all the drugs that are safe to use in people, in particular those with evidence that they may target altered pathways in glioblastoma. And we try to see, using our culture model of glioblastoma, which ones kill cells by arresting growth.”
Riggins’ approach recently got a huge boost. This past fall, a large research team that included Riggins and was led by Johns Hopkins oncologist Bert Vogelstein completed sequencing the 20,661 genes that make up the glioblastoma genome. The scientists, who reported their results in the September 4, 2008 Science, also analyzed the genetic mutations found in the 22 tumor samples used for the study. “What was interesting about the analysis,” says Riggins, “was the sheer complexity of the mutations.” On average, each patient had about 40 different mutations.
Even though the array of mutations is incredibly complex, and no two patients seem to have the same pattern, many glioblastomas appear to have alterations in the same molecular pathways of growth. So alterations in different genes might set off the same molecular cascade that, in the end, leads to uncontrolled growth. “So we may not be able to get a drug for every mutation,” notes Riggins, “but we might be able to target a pathway.”
One that Riggins has explored is called the Akt pathway. He and Johns Hopkins neurosurgeon Gary Gallia have found that genetic mutations activating the Akt pathway are present in at least 85 percent of all glioblastomas. In recent studies, this team identified a small-molecule drug that effectively blocked the Akt pathway in glioblastoma cell lines. His group then tested the compound in a rat model of glioblastoma. The researchers implanted polymer wafers containing the drug near the site of the tumors. They found that animals that had received the drug implants survived for twice as long as a control group of animals.
The results are gratifying but there’s still much more work to be done, says Riggins. An effective therapy against glioblastoma will most likely have to target more than one growth mechanism, which means identifying more than one effective drug. “It is not like trying to design a specific magic bullet,” he says, “It’s like trying to design a cocktail.”