Logic and Lung Cancer

Do people exposed to secondhand smoke experience the same sort of gene silencing in their lung tissue as smokers do?

A study published in Mutagenesis earlier this year found similar DNA methylation patterns in lung tumors of smokers and of never-smokers exposed to secondhand tobacco smoke. But a smoker’s exposure to tobacco smoke is far greater and incurs a much higher cancer risk. Compared with never-smokers, people who currently smoke have a 15- to 20-fold inc

"Smoking damages mainly the lungs, so what better way to counteract that damage than to go in like the smoke itself—through the airways?” says Roman Perez-Soler, M.D., professor of medicine and oncology division chief. Dr. Perez-Soler and his co-investigator, Yiyu Zou, Ph.D., associate professor of medicine (oncology), are using this strategy against lung cancer, which kills about 150,000 Americans each year and is the leading cause of cancer death.

This article originally appeared in the Winter/Spring issue of the Einstein Cancer Center newsletter.Lung cancer is so lethal because it has usually spread to other organs by the time it’s detected. But what if it could be found much earlier? “In smokers, cells in the bronchial epithelium [lung lining] are hit by carcinogen-laden smoke, which damages DNA,” explains Dr. Perez-Soler, who is also associate director of clinical research and co-leader of the Developmental Therapeutics Program at the Albert Einstein Cancer Center, and chair and chief of oncology at Montefiore Medical Center, the University Hospital and academic medical center for Einstein. Damaged lung cells can linger in a premalignant state for many years. Things go wrong, he explains, when cells can no longer prevent bulky chemical units called methyl groups from inactivating tumor suppress or genes that normally put a brake on cell division. These reversible changes to genes are referred to “epigenetic,” in contrast to gene mutations that are permanent—and Drs. Perez-Soler and Zou hope to take advantage of that reversibility.

Follow the Smoke

Their novel therapy involves inhaling a “demethylating” drug called 5-azacytidine. Ideally, it will reactivate tumor-suppressor genes by stripping off the methyl groups that have silenced them. Inhalation therapy is an ideal approach for treating bronchial premalignant lesions and small cancers that have not yet spread: “The drug is toxic, but the doses delivered directly to the damaged tissue in this way are very small,” says Dr. Perez-Soler.

Last year the National Institutes of Health awarded the researchers a five-year, $2.5 million grant to develop this inhalation therapy, “After we determine the highest nontoxic dose, we’ll extrapolate to humans, write a clinical protocol and start treating patients at Montefiore,” says Dr. Perez-Soler.

Early Warning

The first people treated—probably beginning next year—will be patients with lung cancer whose therapy has failed. But the researchers’ ultimate aim is to intervene with inhaled 5-azacytidine at an earlier, premalignant stage. A technique developed by Simon D. Spivack, M.D., M.P.H., professor of medicine (pulmonary medicine), will help identify those people most likely to benefit from the inhalation therapy. Dr. Spivack analyzes the looking for genetic “signatures” indicating that someone is at high risk for lung cancer. Dr. Spivack is also chief of pulmonary medicine at Einstein and Montefiore, and codirector of the Montefiore Asthma Center.

John Greally, M.B., B.Ch., Ph.D, associate professor of genetics, of medicine (hematology) and of pediatrics, has developed a technique called the HELP assay that detects methyl groups at key locations in every human gene. The HELP assay will be used before and after inhalation therapy to reveal whether the therapy is having the desired demethylating effect on genes. Dr. Greally is also the Faculty Scholar for Epigenomics and attending physician in pediatrics at The Children’s Hospital at Montefiore.