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Small Molecule Might Play Big Part in Lung Cancer

High levels of miR-21 were found in nonsmoking patients; could be target for treatment

SATURDAY, July 18 (HealthDay News) -- Researchers have isolated a small molecule that might play a big part in a form of lung cancer that typically strikes people who have never smoked, opening up the possibilities for new treatments for this deadly malignancy.

The microRNA miR-21 was found particularly elevated in adenocarcinomas that affect never-smokers, especially in individuals who tested positive for mutations in their epidermal growth factor receptor (EGFR) gene. Annually, more than 10 percent of lung cancers strike people who never touched a cigarette.

Japanese and American researchers involved in this new study believe that the miR-21 protein is not merely a marker of disease, such as PSA levels are in prostate cancer screenings, but an actual contributor to the cancer process. The findings appear in this week's online issue of the Proceedings of the National Academy of Sciences.

"This is very sophisticated, high-end science," said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society. "It's very intriguing."

Doctors have long known that there are differences in the biology and, ultimately, in the treatment of lung cancers that affect smokers and those that strike people who have never smoked. Among these never-smokers, the most common form of lung cancer is adenocarcinoma, a type of non-small cell cancer that arises in the lungs' peripheral tissues. Non-small cell malignancies make up the majority of U.S. lung cancer cases, followed by small-cell malignancies.

Scientists examined cancer samples from 28 patients, all of them never-smokers who had adenocarcinoma. Compared with tissue samples taken earlier from smokers who had the same disease, miR-21 was noticeably elevated in patients who had never smoked, according to researcher Dr. Curtis Harris, chief of the Laboratory of Human Carcinogenesis at the U.S. National Cancer Institute.

According to Harris, miR-21 is also elevated in tobacco-related adenocarcinoma, but to a lesser extent. Earlier research also showed that elevated levels of miR-21 and other microRNAs were markers for poor survival in smoking-related lung cancer.

All lung cancers are notoriously difficult to treat. They have an overall five-year survival rate of less than 10 percent and kill nearly 160,000 Americans every year. Researchers, therefore, are hopeful whenever they find something in the cancer cell to target with an existing or potential therapy. Two recent targeted therapies for specific lung cancers follow this line of scientific thought -- gefitinib (Iressa) and erlotinib (Tarceva).

To test their hypothesis that miR-21 and EGFR may make attractive targets for therapy, the researchers tested two experimental compounds: an antisense molecule designed to bind to the RNA and essentially turn it off; and a compound called AG1478, which targets the cell's EGFR and tyrosine kinase pathway.

The researchers found that the drugs were most effective in accelerating cancer cell death when used together, suggesting that EGFR plays an important role in miR-21 elevation and cancer creation.

"It's a long road from 'bench to bedside,'" Lichtenfeld said of the findings. "But clearly this study offers the suggestion that there can be an effective treatment for nonsmokers whose adenocarcinoma shows miR-21 elevation."

More information

More on lung cancer can be found at the U.S. National Cancer Institute.

SOURCE: Curtis Harris, M.D., U.S. National Cancer Institute, Bethesda, Md.; Len Lichtenfeld, M.D., deputy chief medical officer, American Cancer Society, Atlanta; July 13-18, 2009, Proceedings of the National Academy of Sciences, online

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