Researchers at Stanford University have reported the startling discovery that tricyclic antidepressants (TCAs) that have been available for decades for treatment of depression may effectively inhibit small-cell lung cancer (SCLC) and other neuroendocrine tumors.
Investigators used “a systematic drug-repositioning bioinformatics approach” to identify drugs already approved by the US Food and Drug Administration for other indications as candidate drugs to treat SCLC. Findings are reported in the journal Cancer Discovery published by the American Association for Cancer Research.
The science of bioinformatics, perhaps best known for the major role it has played in the Human Genome Project, provides databases that enable researchers to submit, search, and analyze vast amounts of information to an extent that previously seemed impossible. In the present study, investigators used a computerized “discovery pipeline” developed in the laboratory of coauthor Atul Butte, MD, PhD, associate professor of pediatrics at Stanford and director of the Center for Pediatric Bioinformatics at Lucile Packard Children’s Hospital. Hundreds of thousands of gene-expression profiles were scanned and analyzed.
Lung cancer is the number one cause of cancer-related deaths in the world, and SCLC -- which accounts for about 15 percent to 20 percent of cases -- “is a very deadly subtype... characterized by the rapid expansion and metastasis of small cells with neuroendocrine features,” the authors noted. Without treatment, patients may survive only a few weeks to months after initial diagnosis. Systemic chemotherapy only improves median survival “to approach a year” and there is currently no approved targeted therapy “despite numerous attempts and clinical trials.”
The investigators found that TCAs and related molecules “potently induce apoptosis in both chemonaive and chemoresistant SCLC cells in culture, in human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC.” TCAs “activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors.” Moreover, said the investigators, "TCAs inhibit growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma.”
Because the drugs are already FDA-approved for use in humans, the researchers have already been able to launch a clinical trial. The phase II trial is recruiting patients with SCLC and other neuroendocrine cancers. “We are cutting down the decade or more and the $1 billion dollars 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.
“It was less than 20 months from the time of our discussion to a clinical trial because the bioinformatics approach had been established and the drugs are FDA-approved,” added coauthor Julien Sage, PhD, associate professor of pediatrics at Stanford. “By focusing on diseases with little hope for the patient, it’s easier to go forward fast.”