New work by researchers in the Kimmel Cancer Center at Johns Hopkins may allow them to halt the smoking-induced cellular events that lead to 99 percent of all small cell lung cancers (SCLC). The research is reported in the March 5, 2003, issue of Nature.
The researchers found that a primitive cellular pathway, called Sonic Hedgehog (named for the cartoon character and spiky hairs it develops on fruit flies) stays turned on long after it should be turned off in some lung cancers.
"We believe chronic injury to the lungs by cigarette smoking re-activates genes in the Hedgehog pathway to repair cell damage in the lining of the lungs. 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," says Neil Watkins, Ph.D., research associate at the Kimmel Cancer Center and lead author of the study.
The Sonic Hedgehog pathway has been well studied for its role in the development of mammalian embryonic cells, and more recently, for its relationship to cancer. Now, Kimmel Cancer Center investigators are testing drugs on mice, including one called cyclopamine, that block the Hedgehog pathway. Human clinical trials are not planned at this time and may be three to four years away.
The scientists analyzed tissue samples and tumor cell lines from SCLC and non-small cell lung cancer (NSCLC) patients. Of ten SCLC tissue samples studied, half showed activation of the Hedgehog pathway and increased expression of one of its targets called the Gli1 gene. They confirmed these findings by looking at SCLC cell lines in which five of seven lines examined showed similar activation of the Hedgehog pathway and Gli1 gene. Limited activation of the pathway was found in NSCLC.
"This study represents one of the first attempts to therapeutically manipulate this cell pathway, and it's a perfect example of how basic developmental science can have clinical implications in a relatively short period of time," says Stephen B. Baylin, M.D., Ludwig professor of oncology and director of research at the Kimmel Cancer Center.
Lung cancer is the leading cancer killer. Close to 172,000 cases are diagnosed each year. Unresponsive to standard therapy, SCLC is the most lethal form of lung cancer. It typically cannot be treated with surgery and though it initially responds to chemotherapy, most patients relapse. "As cigarette smoking persists among young people, we expect to be dealing with this disease for years to come. As a result, the search for potential new therapies are key to controlling this disease," says Watkins.
In addition to Watkins and Baylin, other Johns Hopkins participants in this research include David Berman, Scott G. Burkholder, Baolin Wang, and Philip Beachy.
The research was funded by the Flight Attendant Medical Research Institute and a National Cancer Institute lung cancer SPORE (Specialized Projects of Research Excellence).
Related Web Sites: www.hopkinskimmelcancercenter.org