Stanford University School of Medicine investigators may have discovered a new chemotherapy target for a deadly form of leukemia. A molecular signal, glycogen synthase kinase 3 (GSK3), known to regulate cell growth appears to play a %u201Cdouble agent%u201D role.
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Stanford University School of Medicine
Stanford University School of Medicine investigators may have discovered a new chemotherapy target for a deadly form of leukemia. Researchers observed that a molecular signal, glycogen synthase kinase 3 (GSK3), known to regulate cell growth appears to play a “double agent” role.
The rogue GSK3 signal halts uncontrolled cell growth, preventing several forms of cancer, and keeps the growth of healthy cells in check. The Stanford team compiled new data, however, demonstrating that GSK3 fuels mixed-lineage leukemia (MLL). MLL is a deadly form of white blood cell cancer that accounts for 5% to 10% of leukemia diagnoses in children and adults and more than three-quarters of leukemias diagnosed in infants.
Michael Cleary, MD, professor of pathology, pediatrics, Stanford Cancer Center, and colleagues recently outlined their discovery in the online version of . They found that inhibiting GSK3 combats MLL cancers. Most cases of leukemia originate in one of the body’s white blood cell factories: the lymph nodes or the bone marrow. In MLLs, however, the malignant cells may contain markers from both kinds of tissue. Patients with a new diagnosis of leukemia undergo testing to see which genes are driving the cancer, and Dr. Cleary said that the detection of mutated MLL genes is a bad prognostic indicator.
The findings from Dr. Cleary and associates indicate that GSK3 may constitute an effective target for future leukemia drugs. “This finding was quite unexpected,” he said. “GSK3 has never been implicated in promoting cancer.”
The first hint of GSK3’s role came from laboratory tests on cancer cells. Postdoctoral scholar and study researcher Zhong Wang, PhD, treated Petri dishes containing different kinds of cancer cells with a battery of chemicals known to inhibit various cell signals. When a GSK3 inhibitor clobbered cells that had mutant MLL genes, Dr. Wang realized his work was cut out for him. “I was excited, but I knew I’d have to do lots of work to confirm the finding,” stated Dr. Wang. “Most people say GSK3 cannot be a cancer target,” he added. This belief stems from earlier discoveries that found GSK3 slowed certain malignancies, such as colon cancer.
Dr. Wang conducted an extensive battery of follow-up experiments and confirmed that GSK3 was driving the leukemia cells. For instance, he administered the psychiatric drug lithium—a weak GSK3 inhibitor—to mice with MLL-gene leukemia. The mice treated with lithium survived longer than the untreated mice.
The signal is an especially promising leukemia drug target, the researchers wrote in their recent paper on the subject, because GSK3 typically slows the growth of healthy bone marrow stem cells. Thus, it is possible that treatment with GSK3 inhibitors could have a double-whammy effect on leukemia, killing cancerous white blood cells while promoting growth of healthy stem cells, such as those delivered in a bone marrow transplant. Developing a drug that selectively kills cancer but facilitates the growth of healthy cells would offer a tremendous advantage in treating patients with cancer.
Ultimately, “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,” concluded Dr. Cleary. Now that the team has identified GSK3 as a potential anti-leukemia target, they plan to study how the signal stimulates cancer. Dr. Cleary and colleagues are hunting for high-potency GSK3 inhibitors that could be given safely to humans.