"I was excited, but I knew I'd have to do lots of work to confirm the finding," he said. "Most people say GSK3 cannot be a cancer target." That's because of earlier discoveries that showed GSK3 slowed malignancies such as colon cancer.
But Wang's extensive follow-up experiments confirmed GSK3 drove leukemia. For instance, he gave the psychiatric drug lithium, a weak GSK3 inhibitor, to mice with MLL-gene leukemia. Mice that got lithium lived longer than those that did not.
Now that the team knows GSK3 is a potential anti-leukemia target, they're studying how the signal revs up cancer.
They're also starting the hunt for high-potency GSK3 inhibitors that could safely be given to humans. The signal is an especially promising leukemia drug target, the researchers said, because GSK3 normally slows the growth of healthy bone marrow stem cells. Thus, it's possible that giving GSK3 inhibitors will have a double-whammy effect on leukemia, killing the cancerous white blood cells and promoting growth of healthy stem cells, such as those given in a bone marrow transplant.
"Most current cancer drugs target both the normal and the aberrant cells," Cleary said. It would be a big advantage in cancer treatment if a drug were developed that could selectively kill cancer but help healthy cells grow. Of course, the danger with GSK3 inhibitors would be that they might also cause other cancers if given long-term. Cleary said it's too early to tell if or how a new drug might skirt that problem.
"There will be a lot of hard work required to get better anti-GSK3 compounds, test them in preclinical models and translate them to human trials," he said.
|Contact: Erin Digitale|
Stanford University Medical Center