A little-used class of FDA-approved antidepressants appears potentially effective in combating a particularly deadly form of lung cancer, according to a new study from researchers at the Stanford University School of Medicine.
Since the drugs have already been approved by the U.S. Food and Drug Administration for use in humans, the researchers have been able to quickly launch a clinical trial in patients, cutting development time for a new drug from a decade and $1 billion or more to two years and about $100,000, the authors estimate. The NIH says that number is now more like $5 billion and only a 5 percent success rate.
The phase-2 trial is now recruiting participants with small-cell lung cancer and other, similar conditions like aggressive gastrointestinal neuroendocrine cancers.
Small-cell lung cancers account for only about 15 percent of all lung cancers, but they are particularly deadly. "The five-year survival for small-cell lung cancer is only 5 percent," said Julien Sage, PhD, associate professor of pediatrics. "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 researchers used a computerized discovery pipeline developed in the lab of Atul Butte, MD, PhD, associate professor of pediatrics, who founded and hold shares in a company called NuMedii with former consulting faculty member Joel Dudley, PhD, also a co-author of the paper/ They have licensed the intellectual property described in the study and are further developing the drugs for clinical use. Butte, Sage, Dudley and Jahchan are listed on a patent filed on the use of specific tricyclic antidepressants and related molecules in neuroendocrine tumors.
The pipeline 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.
For example, if a particular molecular pathway is routinely activated (as indicated by an increase in the expression levels of the genes involved) in a cancer cell, and a drug is shown to block or suppress that same pathway (by decreasing the expression of genes in the pathway), it's possible the drug could be used to treat that type of cancer — regardless of the disease for which it was originally approved.
Butte and Sage have had success with this approach before. In 2011, they reported in Science Translational Medicine that an anti-ulcer drug might be effective against a different subtype of lung cancer, and that an anti-seizure drug could be a new way to treat inflammatory bowel disease.
Lead author and postdoctoral scholar Nadine Jahchan, PhD, was interested in small-cell lung cancer. When researchers in the Butte lab used the computerized algorithm to identify possible drug candidates, tricyclic antidepressants were at the top of the list. These drugs are approved to treat depression, but have since been supplanted by newer antidepressants with fewer side effects.
Jahchan tested the effect of a tricyclic antidepressant called imipramine on human small-cell lung cancer cells grown in the laboratory and growing as tumors in laboratory mice. She found that 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, identified by the bioinformatics screen, also exhibited cancer-cell-killing abilities.
Although imipramine did not affect cells from another main type of lung cancer called non-small-cell lung adenocarcinoma, it did inhibit the growth of cells from other neuroendocrine tumors, including pancreatic neuroendocrine cancers, an aggressive skin cancer called Merkel cell carcinoma, and a pediatric cancer called neuroblastoma. (Neuroendocrine cells receive signals from the nervous system and secrete hormones like adrenaline into the blood to affect the body's function.)
Further investigation showed that the drugs appear to work through a class of molecule on the cancer cells' surfaces called G-protein-coupled receptors, but the researchers are continuing to investigate exactly how the drugs specifically kill neuroendocrine cancer cells.
"Our collaboration with the Butte lab allowed us to move very quickly from the initial idea to very convincing results," Sage said. "It was less than 20 months from the time of our first discussion to a clinical trial because the bioinformatics approach had been established and the drugs are FDA-approved. By focusing on diseases with little hope for the patient, it's easier to go forward fast."
Citation: Nadine S. Jahchan, Joel T. Dudley, Pawel K. Mazur, Natasha Flores, Dian Yang, Alec Palmerton, Anne-Flore Zmoos, Dedeepya Vaka, Kim Q.T. Tran, Margaret Zhou, Karolina Krasinska, Jonathan W. Riess, Joel W. Neal, Purvesh Khatri, Kwon S. Park, Atul J. Butte, and Julien Sage, 'A Drug Repositioning Approach Identifies Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors', Cancer Discovery Published OnlineFirst September 26, 2013; doi:10.1158/2159-8290.CD-13-0183