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 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.
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