August 29, 2002
MEDIA CONTACT: Joanna Downer
PHONE: 410-614-5105
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New Possibilities For Treating Childhood Brain Cancer

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 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 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.

On the Web: http://www.sciencemag.org

Public release date: 18-Jan-2007


Contact: Vanessa Wasta
wastava@jhmi.edu
410-955-1287
Johns Hopkins Medical Institutions

Statin plus cancer drug deliver combo punch to brain cancer cells Drugs play on output of genes linked to 'cell-signaling' proteins

Building on newly discovered genetic threads in the rich tapestry of biochemical signals that cause cancer, a Johns Hopkins Kimmel Cancer Center team has dramatically killed brain cancer cells by blocking those signals with a statin and an experimental antitumor drug.

The unlikely pairing of cholesterol-lowering lovastatin and cyclopamine killed 63 percent of medulloblastoma cells grown in the laboratory. By contrast, using either agent alone wiped out fewer than 20 percent of cells. The Hopkins researchers published their findings in the January issue of the American Journal of Pathology.

The researchers caution that the cyclopamine-lovastatin combination has yet to be tested in animals, much less people, but they conclude that the tumor cell-killing by the combo is tantalizing. Cyclopamine works by blocking the so-called "hedgehog" pathway, long known to promote and guide cell and organ growth. Excessive growth is the chief characteristic of cancer. The investigators believe that blocking hedgehog with cyclopamine makes cancer cells more susceptible to lovastatin.

Along with its cholesterol-clogging effects, lovastatin, sold under the trade name Mevacor, is known to curb destruction of proteins that put the brakes on cell growth, causing cancer cells to self-destruct through a process called apoptosis. The effects of the statin already is being studied in people at high risk for the deadly skin cancer, melanoma.

First extracted from corn lilies in the 1950s, cyclopamine is a powerful toxin known to stunt fetal development and cause birth defects in humans and animals. Its connection to anti-cancer efforts grew out of later insights into its blockage of hedgehog, which gets its name from spiky hairs that develop on fruit flies lacking the signal.

"We already knew from earlier research that hedgehog controls brain cell survival and growth, and that blocking signals in this pathway may stop uncontrolled growth of cancer cells," says Charles Eberhart, M.D., Ph.D., associate professor of pathology, ophthalmology and oncology. "But the new work shows the hedgehog blockade may halt another powerful cell-survival signal, and lovastatin could provide the added boost necessary to kill more cancer cells."

Specifically, Eberhart found links between the expression of key hedgehog-related genes in medulloblastoma cells and another cell signal already tied to cancer, Bcl-2. Eberhart and his team believed that combination of a hedgehog blockade and a pro-apoptosis drug like lovastatin would kill more cancer cells.

"Our experiments suggest that hedgehog's action is woven together with Bcl-2, best known for its role in causing B-cell lymphomas," he says. "Cancer cells thwart suicide by overproducing Bcl-2, assuring them a long life."

When the Hopkins researchers noticed that Bcl-2 and hedgehog expression increased in tandem in medulloblastoma cells, they tried adding hedgehog-blocking cyclopamine to the cells and found that Bcl-2 production dwindled and tumor cells died off.

Lead author and pathology fellow Eli E. Bar, Ph.D., said he was "surprised by the degree to which the drug combination was so effective."

According to Eberhart, only half of children with medulloblastoma survive. "And those that do survive can suffer debilitating side effects caused by current toxic therapies."

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The study was supported by the National Institute of Neurological Disorders and Stroke. Coauthors were Aneeka Chaudhry and Mohamed H. Farah.

Links:

Johns Hopkins Kimmel Cancer Center
http://www.hopkinskimmelcancercenter.org

Cancer Cell. 2008 Mar;13(3):249-60.Links
Transient inhibition of the hedgehog pathway in young mice causes permanent defects in bone structure.
Kimura H, Ng JM, Curran T.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.

The Hedgehog (Hh) pathway plays critical roles in normal development and in tumorigenesis. We generated Gli-luciferase transgenic mice to evaluate the Smo inhibitor, HhAntag, by whole animal functional imaging. HhAntag rapidly reduced systemic luciferase activity in 10- to 14-day-old mice following oral dosing. Although pathway activity was restored 2 days after drug removal, brief inhibition caused permanent defects in bone growth. HhAntag inhibited proliferation and promoted differentiation of chondrocytes, leading to dramatic expansion of the hypertrophic zone. After drug removal, osteoblasts invaded the cartilage plate, mineralization occurred, and there was premature fusion of the growth plate resulting in permanent disruption of bone epiphyses.

PMID: 18328428 [PubMed - in process]


http://www.prnewswire.com/cgi-bin/micro_stories.pl?ACCT=159681&TICK=CHOP&STORY=/www/story/03-10-2008/0004771098&EDATE=Mar+10,+2008