Science Editor

Cigarettes are the smoking guns of lung cancer.

They're the leading cancer killer. Close to 172,000 smokers are diagnosed each year in the U.S.

These pulmonary malignancies come in three bronchogenic tumor types: adenocarcinoma, squamous cell carcinoma and small-cell lung cancer (SCLC). "That's a very, very deadly type of tumor," observed cancer biologist Stephen Baylin, at the Johns Hopkins School of Medicine in Baltimore. "SCLC is a smoking-related cancer, and although it responds transiently to chemotherapy, the five-year survival is dismal - only a few percent. It's an extremely lethal tumor."

Baylin is senior author of an article in the latest issue of Nature, dated March 5, 2003. Its title: "Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer." The lead author is post-doc research associate Neil Watkins, at Hopkins' Kimmel Cancer Center.

"We believe chronic injury to the lungs by cigarette smoking re-activates genes on the Hedgehog pathway to repair cell damage in the lining of the lungs," Watkins told BioWorld Today. "The ongoing and regular assault to the lungs by cigarettes causes the usually dormant pathway to be stuck in activation mode, making too many new cells - ultimately resulting in cancer."

Baylin stated: "One key finding of our Nature paper is a developmental biology pathway called the Sonic Hedgehog pathway. This is important to stem cell development in a number of different tissues in a number of different ways. Sonic Hedgehog (Shh) often works as a soluble ligand for a receptor called Patched. When Shh and Patched are acting together, Shh drives the pathway, which results in activation of an oncogenic transcription factor called Gli.

"Often, Shh will be produced by one cell in a developing embryonic system," Baylin told BioWorld Today, "say, the epithelial cells lining the respiratory airways. Something like a lung will form normally. What we found here," he continued, "was that at a particular time window in the developing mouse lung there are cells in the airway lining starting to form the distal airways that branch in the developing lungs."

Hurt Lung, Seed Tumor, Dose Drug, Reap Results

Three main in vivo experimental components that Watkins and his co-authors mobilized to treat nude mice modeling small-cell lung cancer included (1) an industrial chemical, anthracene, to inflict cellular injuries on the inner lung lining, (2) human cancer cells to grow under the skin of the animal's flanks, and (3) a novel therapeutic compound, cyclopamine, to reverse the malignant lesions.

"We adopted the classic approach to growing tumors in mice," Baylin recounted. "They grew under the flanks of the animals, where we could measure their circumference and growth. We let the tumor expand to where we could feel it, and then we did the cyclopamine drug study."

Baylin noted that "in an injury model in the mouse, where we transiently employed anthracine, a chemical that damages the lining of the lung, the mice survived just fine. They repaired this injury. During that repair, we saw reactivation of the situation where the lining cells themselves were producing the Shh and the Gli.

"Having seen that," Baylin continued, "Neil [Watkins] recognized that the cells that do this airway branching early in embryogenesis, or during this repair, often feature a transient neuroendocrine property. He recognized in turn that that kind of activity is well known to go on in 15 percent to 20 percent of human SCLC tumors.

"Our preclinical experiments are dependent not on a mutation, or anything we've been able to find so far," Baylin explained, "but just on overactivity of the Shh pathway. The important clinical aspect of this," he pointed out, "is that our co-author, molecular biologist/biochemist Philip Beachy, here over the years, had recognized that the drug derived from a common weed, the corn lilly, in the western mountains of the U.S. When mother lambs eat this plant," Beachy recounted, "their offspring have a developmental defect that looks exactly like blocking Sonic Hh pathway in a mouse. The embryos have a very typical appearance, with one eye in the middle of the head. The condition is called cyclopia - one-eyed. So the drug extracted from the corn lilly was named cyclopamine.

"When you genetically disrupt Sonic Hh," Baylin pointed out, "cyclopia occurs in the embryos of mice. The embryonic lamb acquires the phenotype when pregnant ewes naturally eat this plant. So cyclopamine is a specific blocker of the Shh pathway. It's not on the market, but there's a company, Curis Inc., of Cambridge, Mass., that has licensed cyclopamine from Hopkins."

Baylin added, "We have some other novel compounds, which may be very important because it may be these derivatives of cyclopamine are even more potent. That may be the final outgrowth if this works clinically. It's a very exciting finding, which will take the usual couple of years to test, but it raises our hopes.

"What we did was block the growth of the SCLC in culture. It very specifically blocked the Shh pathway. And we blocked their growth as explants into the preclinical athymic nude mouse. We dosed mice carrying explants of the SCLC with cyclopamine and observed a marked reduction and cessation of the cancer. Our big, fervent hope is that that there will be activity to get this to people someday and find out if it works clinically."

Pointy-Head Hedgehog Gene Inspired Pathway

"A human clinical trial," Baylin surmised, "may be down the line within a couple of years because there is now going to be very active work moving straight toward the ability to repeat this mouse experiment in humans. It will have to go through the usual work in animals to look at two things: First, which derivative compound will be the best one to use? And second, the usual Phase I toxicity assays. So far, in this preclinical study an overall toxicity was not observed. But we obviously have to work that out extremely carefully."

Baylin concluded parenthetically that "Sonic Hedgehog is the main figure in a popular comic strip or video game that has a fancied resemblance to Shh when they are born with a very pointy head and nose."