Tricyclic antidepressants may be effective against an aggressive lung cancer

A little-used class of antidepressants appears potentially effective in combating a particularly deadly form of lung cancer, according to a new study. Because the drugs are already FDA-approved for use in humans, the researchers were able to quickly launch a clinical trial to test their theory in patients. The phase II trial is now recruiting participants with small cell lung cancer and other similar conditions such as aggressive gastrointestinal neuroendocrine cancers.

The "repositioning" of an existing drug to treat a disorder other than the one for which it was originally approved is an example of how extremely large genetic and biologic databases are changing the face of medicine.

"We are cutting down the decade or more and the $1 billion it can typically take to translate a laboratory finding into a successful drug treatment to about 1 to 2 years and spending about $100,000," said co-senior author Atul Butte, MD, PhD, of Stanford University School of Medicine in California. The study was published in Cancer Discovery (2013; doi:10.1158/2159-8290.CD-13-0183).

Small cell lung cancers account for only approximately 15% of all lung cancers, but they are particularly deadly. "The 5-year survival for small cell lung cancer is only 5%," said co-senior author, Julien Sage, PhD, also at Stanford. "There has not been a single efficient therapy developed in the last 30 years. But when we began to test these drugs in human cancer cells grown in a dish and in a mouse model, they worked, and they worked, and they worked." Specifically, the drugs activated a cellular self-destruct pathway that killed the cancer cells.

The research pipeline these scientists used works by scanning the hundreds of thousands of gene-expression profiles (gathered by multiple researchers and stored in large databases) across many different cell types and tissues—some normal and some diseased, some treated with medications and some not. Alone, these profiles may not mean much to any one investigator or group, but when viewed together, researchers can pick out previously unsuspected patterns and trends.

The researchers tested the effect of imipramine, a tricyclic antidepressant, on human small cell lung cancer cells grown in the laboratory and growing as tumors in laboratory mice. The drug was able to potently activate a self-destruction pathway in the cancer cells and to slow or block metastases in the animals. The drug maintained its effectiveness regardless of whether the cancer cells had previously been exposed, and become resistant, to traditional chemotherapy treatments. Another drug, an antihistamine called promethazine, also exhibited cancer-cell-killing abilities.

Although imipramine did not affect non-small cell lung adenocarcinoma cells, it did inhibit the growth of cells from other neuroendocrine tumors including pancreatic neuroendocrine cancers; Merkel cell carcinoma, an aggressive skin cancer; and neuroblastoma, a pediatric cancer. (Neuroendocrine cells receive signals from the nervous system and secrete hormones like adrenaline into the blood to affect the body's function.)

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