SEATTLE — Aug. 29, 2002 — Below is a press release issued by Johns Hopkins describing a paper scheduled to publish in the Aug. 30, 2002issue of the journal Science. The research project was a joint effort between Dr. James Olson, Fred Hutchinson Cancer Research, and a team of researchers at Johns Hopkins.
As the press release reports, the researchers have shown that the growth of medulloblastoma, the most common form of malignant childhood brain cancer, was stopped by a plant chemical known as cyclopamine.
Olson used tumor samples from seven patients who underwent surgery at Children's Hospital and Regional Medical Center. Initiating the experiment in the operating room, Olson's team placed the excised tumor cells in a laboratory dish and exposed the cells to cyclopamine. Cyclopamine killed up to 99.9 percent of the cancer cells after one week of treatment.
According to Olson, current treatment options of surgery, radiation and chemotherapy are better today, yet a number of children still die from these tumors and often the therapy permanently damages many of those who survive. Drugs like cyclopamine, that block a specific pathway that is critical for medulloblastoma growth, represents the first step toward the goal of replacing toxic therapies such as chemotherapy and radiation.
Researchers at Fred Hutchinson and Children's are leading the way in testing new anti-cancer drugs. In 1999, they pioneered the technique to evaluate potential therapies on patient samples derived during surgical resection. This new approach enables many drugs to be compared directly on patient tumor cells, rapidly accelerating the discovery of new, effective drugs. As an example, one of the drugs that showed promise in this manner will be tested in a national clinical trial for children with brain tumors beginning next year. The pace of going from an idea all the way to clinical trial within three years is basically unheard of when traditional screening methods were used in the past.
The survival rate for medulloblastoma depends on a number of circumstances. If a child is over age three and has a complete surgical resection followed by radiation and chemotherapy, the likelihood of three-year cancer-free survival is about seventy percent. For children with metastatic disease or disease in certain places of the brain, the survival drops to about 50 percent. For children under age three, the outcome remains about 30 percent even after highly aggressive therapy that sometimes includes multiple rounds of chemotherapy combined with infusions hematopoetic stem cells.
The most common brain cancer in children may have an Achilles' heel — the signal from a protein called Hedgehog — according to a report in the Aug. 30, 2002 issue of Science.
Scientists from Johns Hopkins and the Fred Hutchinson Cancer Research Center have discovered that blocking the growth signals from Hedgehog in laboratory experiments stops medulloblastoma tumors in mice and kills medulloblastoma cells taken from human patients.
The Hedgehog gene carries the blueprint for the crucial signaling protein that tells other cells what to become during an embryo's development. If this signal is turned on later in life, Hedgehog can lead to cancer, especially in the cerebellum where medulloblastomas arise, says Philip Beachy, Ph.D., professor of molecular biology and genetics at Johns Hopkins' Institute for Basic Biomedical Sciences.
"Specifically blocking the Hedgehog signal stops the growth of medulloblastoma, but not of some other brain cancers," says Beachy, also a Howard Hughes Medical Institute investigator, who cautions that the findings "still are a long way from being useful clinically."
A few other cancers are also linked to Hedgehog signaling, including rhabdomyosarcoma, a childhood muscle cancer, and basal cell skin cancer, the most common cancer in adults. The effect of blocking Hedgehog on the growth of these cancers has not been evaluated.
To block the signal from Hedgehog in their experiments, a team led by Hopkins pathologist David Berman, M.D., Ph.D., and surgeon Sunil Karhadkar, M.D., used a plant chemical called cyclopamine. Compared to a similar chemical that doesn't block Hedgehog, cyclopamine reduced growth of mouse medulloblastoma cells grown in the laboratory and made tumors implanted in mice get smaller, the scientists report.
The scientists next studied tumor samples taken from seven patients who had surgery to remove medulloblastomas. In laboratory dishes, cyclopamine killed up to 99.9 percent of the cancer cells rather than just halting their growth, says James Olson, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center. The chemical didn't affect single samples of two other kinds of brain cancer.
"Success in the mice was not unexpected because we designed the mouse's tumors to rely on the Hedgehog signal," says Beachy. "But learning that medulloblastoma samples from all seven patients were very sensitive to cyclopamine as well was very surprising indeed."
The cells from these cancer patients had abnormal activation of the Hedgehog pathway, but the scientists don't know whether mutations in the Hedgehog gene are responsible.
"If blocking Hedgehog kills all medulloblastoma cells, that would be tremendously important," says Beachy. "If not, the finding still may lead to better treatment options for those patients whose tumors do have elevated levels of Hedgehog signaling."
Beachy says other Hedgehog blockers will likely be found to kill medulloblastomas, too, and may have better characteristics than the plant compound cyclopamine, initially discovered in the 1960s as the cause of clusters of one-eyed lambs born to flocks of sheep grazing in the West. (Beachy's lab showed in 1998 that the defects resulted from cyclopamine's blockage of Hedgehog's signal in the developing embryo.)
The search for new Hedgehog blockers may be accelerated by research reported in the Aug. 22 issue of Nature. A team led by Beachy describes how two proteins related to Hedgehog actually interact, offering additional ways to try to target Hedgehog's signal.
At the heart of this study are new ways to keep track of the two proteins, known as Patched and Smoothened. Scientists already knew that Patched turns off Hedgehog's signal and Smoothened passes it along. The new research shows that Patched indirectly controls Smoothened's activity, suggesting that Smoothened may be particularly susceptible to blocking by small chemical compounds, Beachy says.
The experiments studying medulloblastoma were funded by the Howard Hughes Medical Institute, the National Institutes of Health, the Burroughs-Wellcome Foundation, the Damon-Runyon Foundation, and the Emily Dorfman Foundation, and by ImmuneX. Authors on the study are Berman, Karhadkar, Beachy, Charles Eberhart, Neil Watkins, James Chen, Michael Cooper, and Jussi Taipale, all of Johns Hopkins School of Medicine; and Andrew Hallahan, Joel Pritchard, and Olson of the Fred Hutchinson Cancer Research Center in Seattle, Wash.
Cyclopamine as a blocker of Hedgehog's signal is patented by Johns Hopkins and licensed to Curis Inc. Under a licensing agreement between Curis and The Johns Hopkins University, the University holds equity in Curis. Beachy, Cooper, Taipale, Chen and the University are entitled to a share of royalties from sales of products related to the research described in this article. All financial aspects of these arrangements are managed by the University in accordance with its conflict of interest policies.
Fred Hutchinson Cancer Research Center
Johns Hopkins Medical Institutions
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Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Fred Hutchinson receives more funding from the National Institutes of Health than any other independent U.S. research center. Recognized internationally for its pioneering work in bone-marrow transplantation, the center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. Fred Hutchinson, in collaboration with its clinical and research partners, the University of Washington Academic Medical Center and Children's Hospital and Regional Medical Center, is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 38 nationwide. For more information, visit the center's Web site at www.fhcrc.org.
Johns Hopkins Medical Institution
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