Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer Interview with:
Dr. Atul Butte, MD, PhD Dr. Atul Butte, MD, PhD


Julien Sage Ph. D Julien Sage PhD
Departments of Pediatrics and Genetics
Department of Internal Medicine, University of California Davis Cancer Center
University of California Davis School of Medicine
Sacramento, California What are the main findings of the study?

Answer: A major finding of the study is the identification of first-generation anti-depressants as possible drugs effective against a lethal subtype of lung cancer, small cell lung cancer.

A second important aspect of this work is the use of a bioinformatics-based drug repositioning pipeline developed by the Butte lab, which allowed us, when combined with advanced mouse models of lung cancer developed by the Sage lab, to identify a novel targeted therapy against SCLC and initiate a clinical trial in less than 2 years. Were any of the findings unexpected?

Answer: The finding that tricyclic anti-depressants have such a strong cell death-inducing activity when applied to neuroendocrine tumors is very surprising because these drugs have been used for many years in large populations of patients and are not known to induce cell death in cells. What should clinicians and patients take away from your report?

Answer: There are no approved targeted therapies for SCLC, and many clinical trials have failed in the last 20 years to identify novel therapeutic approaches. While it is way too early to know if TCAs and related molecules will work in patients, this study provides hope that new candidates can be tested fairly rapidly. The bioinformatics approach helps identify drugs that classical approaches may not have pointed to. This report and some other recent reports tell us that an increasing number of research groups are dedicated to study small cell lung cancer, using faster a more efficient approaches. We certainly hope that this will result in novel therapies in the near future. What recommendations do you have for future research as a result of this study?

Answer: An important future direction of this work is to determine the dose and the regimen for the candidate drugs identified: will it be better to combine these drugs with current therapies or use them before, or after, chemotherapy? The phase 2a clinical trial that Joel Neal has initiated is a dose escalation study to determine what dose can be given to SCLC patients. Once the optimal dose range has been identified, the next key question will be to determine the regimen.

In the lab, we continue to investigate why these drugs induce cell death in neuroendocrine cancer cells. A better understanding of the pathways involved may help identify novel targets for therapy.


A Drug Repositioning Approach Identifies Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors

Nadine S. Jahchan, Joel T. Dudley, Pawel K. Mazur, Natasha Flores, Dian Yang, Alec Palmerton, Anne-Flore Zmoos, Dedeepya Vaka, Kim Q.T. Tran, Margaret Zhou, Karolina Krasinska, Jonathan W. Riess, Joel W. Neal, Purvesh Khatri, Kwon S. Park, Atul J. Butte, and Julien Sage

Cancer Discovery Published OnlineFirst September 26, 2013; doi:10.1158/2159-8290.CD-13-0183