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    Making tumor cells disappear

    Poof! They’re gone. In the lab, scientists find a way to transform brain tumor cells into normal brain cells.

    Stopping brain tumor cells from growing sounds like a dream. Turning those cells into normal brain cells sounds like a fantasy. But scientists at St. Jude Children’s Research Hospital are in the process of turning fantasy into reality.

    A team of researchers led by Martine Roussel, PhD, of Genetics and Tumor Cell Biology, discovered that three proteins called BMP2, BMP4 and BMP7 can stop the growth of brain tumor cells and turn them into normal brain cells. The discovery suggests a safer way to treat medulloblastoma, a rare but often fatal childhood brain tumor.

    Disappearing act

    Medulloblastoma occurs in the cerebellum, which is located in the lower, rear part of the brain. The cancer strikes about 350 children in the United States annually. The researchers’ finding is important because, although treated patients have an overall five-year survival rate of 70 percent, conventional therapies combining surgery, irradiation and chemotherapy frequently lead to permanent neurocognitive impairment.

    “We think we have identified a pathway that can be used to prevent tumor formation and a potential target for therapy,” Roussel says. “This means that this pathway could be targeted for treating medulloblastoma. This is exciting because those BMP proteins induce differentiation.” 

    Differentiation is the process by which cells or tissues change to a more specialized form or function.

    “The cells will differentiate and then disappear,” Roussel explains. “A lot of the chemotherapeutic drugs attack the cell by creating DNA damage. Here, you force them to become neurons that cannot be tumor cells anymore. The cool thing is that it can happen only in tumor cells because the neurons that no longer divide cannot be attacked by BMPs. So, this potential drug would specifically attack tumor cells and not the surrounding normal neurons.”

    Protecting bones with BMP

    The laboratory finding that BMP proteins can reverse brain cancer comes several years after other St. Jude researchers showed that an experimental drug called HhAntag is effective at eliminating medulloblastoma cells without the use of chemotherapy or radiation. But then researchers discovered that HhAntag treatment interferes with bone growth.

    Would it be possible to reduce the level of HhAntag and still have a good treatment? Roussel and her team found that using a lower dose of HhAntag in combination with BMP may provide the same therapeutic effect as giving high doses of HhAntag.

    Therefore, clinicians might one day be able to use reduced levels of both compounds, preventing the harmful effects on bone growth while reducing the amount of BMP needed for therapy.

    “The only drawback for the BMPs is that they are important for bone development and, since we would treat kids with this disease who are in their growth phase, we would have to conduct further research to see how this would affect their growth,” Roussel says.

    When pathways converge

    Several research teams are also studying the intricate signaling mechanisms that govern the rapid increase of cells called granule neuron progenitors (GNPs). These cells develop into neurons in the cerebellum during the first year of life. But disruption of this differentiation can trigger medulloblastoma.

    “We were interested in whether there were signals that inhibited tumor formation,” Roussel says. “And if there were, which ones were they? Could they be used to identify new therapeutic targets?”

    Previous research had shown that spurring GNPs to differentiate into neurons requires that the BMPs bind to receptors on the cell surface. This, in turn, blocks the activity of a signaling pathway triggered by another molecule called Sonic hedgehog.

    “We found that the effect of BMPs on normal GNP cells is almost exactly mimicked in GNP-like tumor cells,” Roussel says. “We knew from the published literature that the BMP were antagonizing Sonic hedgehog. But, no one had shown this in tumor cells.”

    The researchers showed that the antagonism was not on the Sonic hedgehog pathway itself, but occurred downstream from that pathway. Both of those pathways seem to work in concert, converging into a protein called Math1, a transcription factor that helps control gene expression.

    The Math test

    In cell culture experiments, Roussel’s group found that BMPs rapidly cause the degradation of Math1, which occurs in dividing GNPs, but not in non-proliferating neurons. After BMP treatment, researchers could detect no Math1, and cell growth soon stopped.

    “People had never before linked the BMP signaling pathway to the Math1 signaling protein,” Roussel says. “We knew there was a correlation between the expression of this transcription factor and proliferation, but nobody knew how this protein was regulated. The direct link between BMP and Math1 allowed us to speculate that if we use BMP as a drug, it could be used to inhibit tumor formation. We found this to be true in the lab.”

    The exact way Math1 works remains unknown. However, research has shown that the protein is vital to the formation of a normal cerebellum.

    All of these recent, novel discoveries create leads for many more types of experiments.

    “The most speculative but exciting project is that we are screening for new, small-molecule BMP agonists with the St. Jude Chemical Biology and Therapeutics department,” Roussel says. An agonist is a drug that triggers an action from a cell.

    “We formed a collaboration with Dr. Taosheng Chen from Chemical Biology and Therapeutics in order to screen chemical libraries,” Roussel says. “If we can find agonists, we will test them in a pre-clinical setting. If any of them are successful, companies might want to go further with it.”

    More BMP protein discoveries could one day lead to treatments for tumors other than medulloblastoma.

    “There was a paper published in the journal Naturein 2007 demonstrating that cancer stem cells from glioblastoma could be inhibited in their growth with the same BMPs,” Roussel says. “So, there is a potential for usage not only for medulloblastoma but for other brain tumors.”

    Reprinted from Promise, Summer 2008

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