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Bioinformatics-based Drug Repurposing Study Suggests Antidepressant May Be Effective Against Lung Cancer

NEW YORK (GenomeWeb News) – By combing through drugs that have already undergone the approval process, researchers led by Stanford University's Julien Sage found that two therapies usually prescribed to treat depression may also help combat small-cell lung cancer, as they reported in Cancer Discovery today.

The researchers' bioinformatics-based drug repositioning approach homed in on a tricyclic antidepressant, imipramine, and an antihistimine and anti-anxiety drug called promethazine, both of which they found to induce apoptosis in SCLC cells. The drugs likely work by disrupting autocrine signaling initiation through binding G protein-coupled receptors on the cancer cells' surfaces. The researchers added that a phase IIa clinical trial based on their findings is underway, underscoring the power of such an approach.

"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," Sage, the senior author and associate professor of pediatrics and genetics at Stanford, said in a statement. "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."

Small-cell lung cancer causes some 1.3 million deaths a year, according to the World Health Organization. Current therapies can improve median survival by about a year, but targeted therapies have been difficult to develop. Repurposing approved drugs, the researchers argued, would save time and money as the therapies have already gone through safety, dosage, and toxicity studies.

To identify potential SCLC drugs, Sage and his colleagues compared gene expression profiles of a number of different cell types in response to a variety of drugs approved by the US Food and Drug Administration. From this, they developed a list of drugs predicted to be effective against SCLC.

The top-ranked drugs affected targets and pathways involved in calcium signaling and neuroactive ligand receptor interactions — pathways where SCLCs, the researchers pointed out, are known to express molecules.

From the list, the researchers focused on six drugs targeting either one of those two pathways for analysis in cell culture models of lung cancer and controls. Four of those six drugs inhibited the growth of both mouse and human SLCS, but not non-small cell lung cancer in culture.

Based on further mouse model studies, the researchers found that the drugs imipramine and promethazine were effective at stopping tumor growth. In addition, they found that treating mutant mice with these drugs lowered their tumor burden as well as the tumor area in the lungs. Also, in a separate mutant mouse model, they discovered that these drugs further appeared to be effective against tumors that had already been treated with the standard cisplatin chemotherapy.

The drugs, Sage and his colleagues reported, appear to work by inducing stress and apoptosis in tumor cells. While the drugs act on a number of targets, the researchers said that their action on G-protein coupled receptors likely affect downstream autocrine survival signaling, bringing about cell death.

In particular, the drugs seem to impair the Gαs adenyl cyclase/cAMP/protein kinase A module activity and induce apoptosis by activating the JNK/c-Jun module.

Because the drugs work on multiple targets they may be a boon for patients and clinicians, the researchers added. "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," Sage said.

Other neuroendocrine cancers, including neuroblastomas and pancreatic neuroendocrine tumors, rely on similar signaling networks, indicating to the researchers that those cancers, too, may be sensitive to similar drugs.

Sage and his colleagues also noted while they have a stage IIa trial of desipramine — a drug similar to imipramine — underway in SCLC and other high-grade neuroendorscrime tumors, final results are still years away.

Still, they suggested that imipramine and related drugs could be useful as refractory or maintenance drugs following chemotherapy.

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