The Johns Hopkins Gazette: September 11, 2000
September 11, 2000
VOL. 30, NO. 2


Molecule Causing One-Eyed Sheep Is Also Cancer Pathway

By Marjorie Centofanti
Johns Hopkins Gazette Online Edition

Scientists at Johns Hopkins and the Howard Hughes Medical Institute have shown, in mouse cells, that they can shut down a cell pathway that's key to several human cancers and can apparently reverse the shift into unrestrained cell division typical of malignancy. The cancers include basal cell carcinoma, the most common type of skin cancer.

In the new study, mouse fibroblast cells engineered to divide uncontrollably reverted to normal with addition of cyclopamine, a chemical extracted from plants in western sheep pastures. The study appears in the Aug. 31 issue of the journal Nature.

The research team used cyclopamine to block mutations known to turn on a biochemical pathway--known to biologists as the Hedgehog response pathway--usually active only in developing embryos. The abnormal switching on of this pathway in adults is linked with basal cell carcinoma, the most common cancer in Caucasians. It's also linked with rhabdomyosarcoma, a highly malignant muscle tumor in children, and with medulloblastoma, a common childhood brain tumor.

Though scientists at pharmaceutical companies and other labs worldwide also are teasing out cancer pathways and finding ways to block them, this study is one of few published accounts of such an approach, and the first centering on this particular pathway.

"The cancer therapy of the future, we believe, now lies with mechanism-based approaches," says Philip A. Beachy, a professor in the Department of Molecular Biology and Genetics, School of Medicine, and an associate investigator with HHMI, who led the team. "That means you search for what's often a single process gone awry in a cell and try to fix or compensate for it. "The aim is to develop a drug that specifically targets that process or pathway, instead of the usual approach of killing all growing cells--what we've done for years with chemotherapy. Our study is very basic; I want to make that clear," Beachy says, "but we've singled out the pathway, and in this work shown it can be turned off in mouse cells, reversing the continuous, unrestrained cell growth."

Cyclopamine first appeared in the 1950s when scientists investigated complaints by Colorado farmers about a spate of births of one-eyed lambs. Pregnant sheep left to pasture had eaten wild corn lilies, high in cyclopamine. Researchers later learned that the chemical interferes with the Hedgehog response pathway, which in embryos directs the future positioning of eyes and appendages.

In the Nature study, the researchers focused on two genes in that pathway. The first, called smoothened, trips a whole cascade of reactions to make cells grow and divide. A second gene, patched, normally acts like a brake, to damp down smoothened's activity in adults. In embryos, however, patched becomes silenced by activity of a master gene called hedgehog, in effect releasing patched's braking activity. Turn on hedgehog, Beachy says, and that silences patched, letting smoothened and subsequent developmental reactions proceed full tilt.

In a series of experiments, the researchers created mouse cells with the patched genes knocked out. These cells mimicked known cancer mutations; cells divided without control. The scientists also created mouse cells in which smoothened had a known cancer-causing mutation. "Those cells, too, proliferated abnormally," Beachy says.

"But when we added cyclopamine or an even more potent variation of the drug," Beachy says, "the Hedgehog pathway shut down and cell division stopped."

"We're not sure exactly how cyclopamine works," Beachy adds, "but we suspect that it somehow affects the smoothened gene's product, making it inactive. This means cyclopamine or a derivative might be quite useful at some point in cancer therapy. And because it's targeted specifically to pathways we believe are active only in adults with cancer, such a therapy, in theory, should have fewer side effects."

Other researchers in the study were Jussi Talpale, James K. Chen, Michael K. Cooper, Baolin Wong and Randal K. Mann, at Hopkins, and Ljiljana Milenkovick and Matthew P. Scott with the Howard Hughes Medical Institute, Stanford University.

The research was funded by the Howard Hughes Medical Institute.