Repurposed Antidepressants May Have Potential to Treat Small Cell Lung Cancer
A bioinformatics approach to repurposing drugs resulted in identification of a class of antidepressants as a potential new treatment for small cell lung cancer, according to a study published in Cancer Discovery.
Based on data generated using bioinformatics, two drugs approved by the U.S. Food and Drug Administration to treat symptoms of depression, imipramine and promethazine, were tested on small cell lung cancer cells and animal models. Imipramine modulates the activity of certain hormones causing mood disorders, and promethazine is a sedative, antiemetic, and antipsychotic drug. Both antidepressants were found to induce small cell lung cancer cell death. They were also effective in mice bearing human small cell lung cancers that had become resistant to the cisplatin.
“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.”
“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,” Dr. Sage added. “We are in the process of identifying the optimal treatment regimen for patients with small cell lung cancer and modifying these drugs to prevent them from entering the brain, in order to minimize side effects.”
Small cell lung cancer is a subtype of lung cancer of neuroendocrine origin, and patients diagnosed with small cell lung cancer have a dismal prognosis. There is currently no approved targeted therapy for small cell lung cancer and no new drugs have been identified in the last few decades.
Study Details
Dr. Sage and colleagues focused their search on drugs targeting the two top pathways identified using a bioinformatics approach: the neuroactive ligand receptor interaction pathway and the calcium signaling pathway. Of the six antidepressants initially shortlisted, imipramine and promethazine emerged as successful candidates for further study based on the results of experiments using small cell lung cancer cell lines and mice bearing human small cell lung cancer tumors.
The researchers then generated mutant mice bearing cisplatin-resistant small cell lung cancer tumors and found that the growth of chemotherapy-resistant tumors was inhibited by imipramine, suggesting that the identified antidepressants will be effective against small cell lung cancers in patients who developed resistance to standard chemotherapy.
They conducted further experiments and found these two drugs acted on small cell lung cancers primarily by inducing cell death mechanisms within the cancer cells. They also found that small cell lung cancer cells express certain receptors called GPCRs, and imipramine and promethazine caused cell death by engaging these receptors and their downstream signaling mechanisms.
Potential for Treatment in Other Neuroendocrine Cancers
Because imipramine was also effective in an animal model of pancreatic neuroendocrine tumors, the researchers are hoping their observations with small cell lung cancer can be extended to a number of other neuroendocrine cancers.
Based on their preclinical results, the researchers have initiated a phase IIA clinical trial to test desipramine, a drug similar to imipramine, in small cell lung cancer and other high-grade neuroendocrine tumors.
This study was funded by the Lucile Packard Foundation for Children’s Health, the United States Department of Army, the NLM Biomedical Informatics Training Grant to Stanford University, the National Cancer Institute, the Stanford Dean’s Fellowship, NRSA T32 Academic Research Training in Pulmonary Medicine, a California TRDRP postdoctoral fellowship, and a Stanford Cancer Institute Developmental Cancer Research Award.
The intellectual property from this work has been licensed to NuMedii, a company further developing these drugs.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
