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    Drug shows a new effect that can control a childhood cancer

    Andrew M. Davidoff, MD

    The drug bevacizumab is widely used to inhibit blood vessel growth in tumors, starving them of oxygen and nutrients. St. Jude researchers have found that the drug also shows promise for attacking neuroblastoma cells themselves. The cause of about 7 percent of childhood cancers, neuroblastoma is responsible for 15 percent of pediatric cancer deaths.

    Andrew Davidoff, MD, Surgery, and his colleagues published their findings in the August 2008 issue of the journal Surgery.

    Bevacizumab’s most well known function is to block the receptor for a protein called VEGF in endothelial cells. Receptors are switches that reside in the membranes of cells and respond to protein signals. When the VEGF protein binds its receptor on the endothelial cells, like a key fitting a lock, it triggers blood vessel growth or angiogenesis, which nourishes the tumor. However, findings by other researchers suggested to Davidoff and his colleagues that VEGF may play a second, more direct role in cancer cell survival.

    “VEGF receptors have been identified on neuroblastoma cells and other tumor cells, suggesting that tumor cells themselves may depend, at least in part, on VEGF stimulation for their survival,” he said. “Our hypothesis was that by inhibiting VEGF, we could not only attack the blood vessels that tumors depend on, but the tumor cells themselves.”

    To explore this possible second effect of bevacizumab, the researchers first tested the drug’s effects on human neuroblastoma cells. Their analysis showed that the cancer cells do, indeed, have receptors for VEGF, and treating neuroblastoma cells with bevacizumab reversed the stimulation of these cells by VEGF.

    “By treating tumor cells grown in tissue culture, where their survival does not depend on blood vessels, inhibition of the growth of the tumor cells could only have been because of the action of bevacizumab on the neuroblastoma cells themselves,” Davidoff said.

    To test whether the drug might also have a cancer-suppressing effect in humans, the researchers next gave bevacizumab to mice that had received human neuroblastoma cells. Importantly, the investigators tested the drug on mice that had only recently received the cells.

    “In this minimal disease state, the tumors were probably surviving without having established their own vasculature, so we could take the well-known anti-angiogenesis mechanism of bevacizumab out of the equation,” he said.

    The researchers found that bevacizumab treatment in the mice significantly reduced their tumors and increased their survival. This finding suggests a useful role for the drug in suppressing neuroblastoma in children.

    “Neuroblastoma can often be knocked down to a level of minimal disease by chemotherapy, surgery and radiation treatment,” Davidoff said. “Then, the problem is eradicating this minimal disease, or at least keeping it at bay. Our findings indicate that bevacizumab is a potentially useful drug for managing this level of disease.” However, Davidoff noted, cancer cells may be able to develop a resistance to the drug.

    “We think it likely that bevacizumab will be most useful in combination with other drugs, such as those that are toxic to cancer cells,” Davidoff said. He and his colleagues are exploring the effects of such combinations on neuroblastoma.

    Other St. Jude authors of this paper include Thomas Sims, MD, Cathy Ng, Yunyu Spence and Regan Williams, MD, all of Surgery, and former St. Jude employee Shannon Rosati.

    This research was supported in part by the Assisi Foundation of Memphis, the U.S. Public Health Service, the National Cancer Institute and ALSAC.

    October 2008