Cyclops and Cancer

In the 1950s, shepherds in Idaho noticed a disturbing trend: large numbers of sheep were giving birth to one-eyed lambs. Scientists investigating the mystery eventually determined that mothers of these “Cyclops sheep” had grazed on a plant called the corn lily, commonly found in Western mountain meadows.

Corn lilies, they learned, contain a compound that blocks a chain of biochemical reactions important to embryonic development, interrupting the signaling pathway meant to tell sheep embryos to develop two eyes, not one. In the 1990s, scientists discovered that same series of reactions—dubbed the “sonic hedgehog pathway” after a popular video game character—also had another important role. When it was inappropriately activated in an adult, it could lead to cancers of the skin, prostate, lung, and pancreas. Perhaps, they reasoned, the corn-lily compound that produced one-eyed lambs—called “cyclopamine”— might also interfere with the sonic hedgehog pathway’s ability to cause cancer.

Last fall, UTMB assistant professor Jingwu Xie (pronounced “see”) showed that cyclopamine can do just that. In an experiment that marked the first successful drug treatment in experimental animals of the most common cancer to afflict human beings—the skin cancer known as basal cell carcinoma (BCC)—Xie used orally administered cyclopamine to dramatically retard tumor development in mice.

“We showed 90 percent fewer BCC tumors after treating with cyclopamine, and 50 percent fewer visible tumors,” Xie says. “Based on the microscopic tumor results, we see a potential to prevent new tumors from developing, while the visible tumor reduction shows us that this can be used for treatment. And since there’s no noticeable toxicity in mice, this therapy has great clinical promise.”

Because cyclopamine kills tumor cells by breaking only a single link in the sonic hedgehog pathway, Xie thinks it will have far fewer side effects than more traditional chemotherapies. And since sonic hedgehog also has been implicated in other cancers, Xie and other researchers believe that cyclopamine or a cyclopamine-like compound that shuts it down could serve as a weapon against more than just BCC.

“We used drinking water to deliver the drug to the mice, and from drinking water to the circulatory system to the skin there are a lot of barriers,” Xie says. “If you can treat skin tumors with an orally administered drug, you should be able to treat other kinds of tumors, too— gastrointestinal tumors, prostate cancers, lung cancers, and some breast cancers.”—Jim Kelly