Science Article
September
5, 2002
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 Science.
Dr. James Olson of the Clinical Research Division, and scientists from Johns Hopkins 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.
To test the blocking of Hedgehog signals, Olson used tumor samples from seven patients who underwent surgery at Children's Hospital and Regional Medical Center. Initiating an operating-room experiment, Olson's team placed excised tumor cells in a laboratory dish and exposed the cells to cyclopamine, a plant chemical patented by Johns Hopkins and licensed to Curis Inc.
Cyclopamine killed up to 99.9 percent of the cancer cells after one week of treatment. The chemical didn't affect single samples of two other kinds of brain cancer.
First step toward goal
While current treatment options of surgery, radiation and chemotherapy are effective, Olson said some children still die from these tumors, and often the therapy permanently damages those who survive. Drugs like cyclopamine that block a specific pathway critical for medulloblastoma growth represent the first step toward the goal of replacing toxic therapies such as chemotherapy and radiation.
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, said Dr. Philip Beachy, molecular biology and genetics professor 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," said Beachy, 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 Dr. David Berman and surgeon Dr. Sunil Karhadkar used 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.
"Success in the mice was not unexpected because we designed the mouse's tumors to rely on the Hedgehog signal," Beachy said. "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," Beachy said. "If not, the finding still may lead to better treatment options for those patients whose tumors do have elevated levels of Hedgehog signaling."
Other blockers likely
Beachy said 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 said.
