Editors' ChoiceCancer

An Anti-Depressing Discovery for Lung Cancer Treatment

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Science Translational Medicine  16 Oct 2013:
Vol. 5, Issue 207, pp. 207ec170
DOI: 10.1126/scitranslmed.3007757

Small cell lung cancer (SCLC) is a subtype of lung cancer with a poor 5-year survival rate (~5%). SCLC is typically treated with combination chemotherapy, which produces impressive initial response rates. Unfortunately, almost all tumors develop resistance to these treatments. Despite extensive efforts, there are currently no targeted therapies approved for SCLC. Jahchan and colleagues used an innovative bioinformatics approach to identify potential therapies for SCLC by analyzing the gene expression signatures of Food and Drug Administration (FDA)–approved compounds and predicting their efficacy against SCLC. Interestingly, tricyclic antidepressants (TCAs) and other compounds that block heterotrimeric guanine nucleotide–binding protein–coupled receptors (including neurotransmitters) were at the top of the list. This result may not be as surprising as it first sounds, because SCLC is a neuroendocrine tumor that expresses the neurotransmitters blocked by these drugs.

The authors showed that two FDA-approved compounds, imipramine and promethazine, caused tumor cell death and inhibited the growth of SCLC in a genetic mouse model and in human SCLC cell lines transplanted into mice. Importantly, imipramine demonstrated efficacy against tumors that were previously exposed to chemotherapy, indicating that it might also be effective against chemoresistant tumors in patients. The results of this study suggest that the tested agents may also be effective against other neuroendocrine tumors, including pancreatic neuroendocrine tumors, Merkel cell carcinoma, neuroblastoma, and more. On the basis of these findings, a Phase IIa clinical trial testing increasing doses of a related TCA, desipramine, is currently under way for patients with SCLC and other high-grade neuroendocrine tumors. Although results of this trial are years away, if successful, this approach will have greatly expedited the use of these approved drugs for treatment of SCLC.

It remains unknown whether TCAs or related drugs could provide protection against SCLC in a preventative setting. Further studies will also be required to elucidate exactly why these drugs are effective, but this knowledge promises to improve treatment options and survival of patients with this deadly disease.

N. S. Jahchan et al., A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov., published online 27 September 2013 (10.1158/2159-8290.CD-13-0183). [Abstract]

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