September 27, 2013
Uncommon Antidepressants Could Become Cancer Treatments
Michael Harper for redOrbit.com - Your Universe Online
Two antidepressants that aren’t often prescribed to patients could soon be recommended to serve a completely different purpose; ward off small-cell lung cancer (SCLC).A new bioinformatics study has found these FDA-approved medications are molecularly predisposed to treat SCLC. By investigating the biochemical foundation of these medications, researchers may be able to repurpose the drug without the lengthy and expensive process of creating a new medicine. The antidepressants imipramine and promethazine will now head into phase 2a clinical trials to test its effectiveness against SCLC and other neuro-endocrine tumors.
The research, conducted by doctors in California and Pennsylvania, is now published online in Cancer Discovery.
“We implemented a bioinformatics-based drug repositioning approach toward accelerated evaluation of FDA-approved drugs for cancer treatment. From the day we started this project, it took less than 20 months to initiate a clinical trial,” said senior author Julien Sage, associate professor of pediatrics and genetics at Stanford University School of Medicine in California. “This is a good example of how we can combine ‘big data’ and the mature field of preclinical animal models to rapidly find new uses for old drugs.”
According to the researchers, SCLC is a relatively rare and deadly form of lung cancer. Though it only accounts for 15 percent of all lung cancers, only five percent of those who develop SCLC survive five years after diagnosis. This is partly due to the lack of an effective medication to fight off the small cell tumors. Sage now says his team's study have shown the two antidepressants could be promising.
“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.” Sage notes these medicines work by activating a sort of self-destruct switch in the cancer cells.
This research, conducted in the labs at the Center for Pediatric Bioinformatics at Lucile Packard Children’s Hospital at Stanford, employed a computer program which scans the hundreds of thousands of gene-expression profiles of cells and tissues. Each researcher lumped their data into a large pool to get a better view of how well each antidepressant treated SCLC. According to the researchers, the computer program is a key component in this study. While the individual profiles of each cell might not yield much data, seeing a multitude of profiles together can draw a better picture.
Sage and team grew SCLC tumors from human cells in the lab and also tested the effects of the antidepressant medicine in mice that had been implanted with SCLC cells. In these tests the antidepressants -- specifically imipramine -- worked by activating certain receptors that triggered a death mechanism in the cells. This not only kills the cells, but also stops the cancer from developing immunity to the medicine.
“Unlike most targeted therapies, which are often specific for a single molecule or pathway, the drugs we identified target multiple receptors at the surface of neuro-endocrine cancer cells, which may make it difficult for cancer cells to develop resistance,” said Sage.
“We are in the process of identifying the optimal treatment regimen for patients with SCLC and modifying these drugs to prevent them from entering the brain, in order to minimize side effects,” he added.
Sage and his colleague Atul Butte, MD, PhD have used bioinformatics before to use an anti-seizure medicine to fight inflammatory bowel disease.