STANFORD, Calif.—According to a new study from researchers at the Stanford University School of Medicine who used a bioinformatics-based approach to identify U.S. Food and Drug Administration-approved drugs for repurposing, a certain class of antidepressants may be effective in combating a particularly deadly form of cancer.
Using an approach like this, sifting through already approved drugs, the Stanford researchers have been able to quickly launch a Phase II clinical trial, in which they are recruiting patients who have small-cell lung cancer and similar conditions, such as aggressive gastrointestinal neuroendocrine cancers.
The results of the study were published online Sept. 27 in Cancer Discovery. The lead author of the paper is postdoctoral scholar Dr. Nadine Jahchan, and the co-senior authors are Dr. Atul Butte, the division chief of systems medicine and director of the Center for Pediatric Bioinformatics at Lucile Packard Children's Hospital at Stanford University, and Dr. Julien Sage, an associate professor of pediatrics. The principal investigator of the clinical study is Dr. Joel Neal, an assistant professor of medicine at Stanford.
“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 one to two years and spending about $100,000,” said Butte in a news release issued by Stanford about the work.
“We’re all happy about how well this bioinformatics approach works,” Jahchan tells DDNews. “We can get to drug trials without taking 10 years and tens of millions of dollars minimum to get there. The approach is very effectively predictive and allows us to move forward more quickly and confidently.” She adds that the approach is not limited simply to cancer indications, although that was the focus of the paper and the clinical work going forward right now.
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 Sage in the news release about the study. “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, Stanford reports, and the university cites the work by the team as evidence of how extremely large genetic and biological databases are changing the face of medicine.
According to the university, the researchers used a computerized discovery pipeline developed in Butte’s lab. Butte and former consulting faculty member Dr. Joel Dudley, also a co-author of the paper, founded and hold shares in a company called NuMedii, which has licensed the intellectual property described in the study and is 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.
Using the bioinformatics technique, the team scanned hundreds of thousands of gene-expression profiles across many different types of normal and diseased cells and tissues. It is an approach with which Butte and Sage had seen previous success back in 2011 when they published in Science Translational Medicine that a drug to combat ulcers might be effective against a different subtype of lung cancer, and that an antiseizure drug could treat inflammatory bowel disease.
Jahchan led the effort to tackle small-cell lung cancer in this case, using the same techniques, and the algorithm to identify possible drug candidates brought tricyclic antidepressants right to the top of the list.
Reportedly, after testing the tricyclic antidepressant imipramine on human small-cell lung cancer cells grown in the lab as well as in mouse models, the drug not only activated a self-destruct pathway in the cancer cells but also seemed to slow or block metastases in the animal models. Moreover, the drug reportedly maintained its effectiveness regardless of whether the cancer cells had previously been exposed to chemotherapy and become resistant to such traditional treatments.
Although imipramine did not affect cells in non-small-cell lung cancer, Stanford notes 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. 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.
