Employing a bioinformatics-based drug approach, researchers at the Stanford University School of Medicine found that imipramine and promethazine, both already approved by the FDA for the treatment of depression, were effective at killing human, chemotherapy-resistant small-cell lung cancer (SCLC) cells placed in mice.
“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 Julien Sage, PhD, 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.”
By focusing on drugs targeting the two top pathways identified using a bioinformatics approach, Sage’s team identified two effective the two successful candidates for further study.
They generated mutant mice bearing SCLC tumors resistant to the chemotherapy drug cisplatin, discovering that tumor growth was inhibited by imipramine, suggesting the identified antidepressants will be effective against SCLCs in patients who developed resistance to standard chemotherapy.
Subsequent experiments revealed the 2 drugs acted on SCLCs primarily by inducing cell death mechanisms within the cancer cells. They also found that SCLC cells express certain receptors called GPCRs, and imipramine and promethazine caused cell death by engaging these receptors and their downstream signaling mechanisms.
“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 neuroendocrine 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.”