Small cell lung carcinoma (SCLC) accounts for about 15% of lung cancers, but it is the deadliest form of lung malignancy. Only 6% of patients with SCLC survive beyond 5 years after diagnosis. In the last few years, new therapies—targeted therapies in particular—have been developed and approved by the U.S. Food and Drug Administration (FDA) for treating other, more common forms of lung cancer such as adenocarcinoma. However, not much progress has been made in addressing SCLC, which is usually treated with a combination of fairly toxic chemotherapeutics and radiotherapy. Many patients respond to these harsh treatments (ie, their tumors shrink), but only transiently. The disease recurs within a few months to 1 year and, at that point, is no longer treatable.
Last week, Cancer Commons’ Chief Scientist Emma Shtivelman wrote about a novel targeted therapy drug for SCLC. This week she covers another exciting SCLC drug that is currently being tested in a clinical trial.
A recent study investigating a potential treatment for SCLC is based on the ‘drug repositioning’ approach, that is, trying to find new indications for existing drugs. This approach is attractive because drugs that are already approved for treatment of some health conditions can enter clinical trials without the need to undergo safety testing, thus greatly accelerating clinical investigations.
In the study published in the journal Cancer Discovery in late September, 2013, researchers in California from Stanford University and UC Davis Medical Center took a computational approach to identify existing drugs that could target the cellular processes activated in SCLC. SCLC is a neuroendocrine cancer, meaning that unlike other types of lung cancer, these tumors exhibit characteristics of neuronal endocrine cells. As such, they express neuroactive molecules and have strong reliance on calcium signaling. Computational analysis of a gene expression database containing data from multiple SCLC tumors identified genes and pathways relevant to the neuroendocrine character of SCLC. Then, computational analysis of a database of existing drugs identified known drugs affecting these pathways.
The top-scoring drugs found in this double-pronged investigation belong to the category of tricyclic antidepressants (TCAs). Starting in the 1950s, TCAs were developed to treat clinical depression, but they have since been almost entirely displaced by newer antidepressant drugs. The authors of the paper also investigated the mechanisms through which TCAs kill SCLC cells and discovered the involvement of proteins known as G-protein-coupled receptors, which are expressed on SCLC cells.
Two of the TCA drugs identified in the study, imipramine and clomipramine, showed strong activity against human and mouse SCLC cells in the lab and in mouse models of SCLC. Not surprisingly, the drugs were completely inactive in killing lung cancer cells from a different type: adenocarcinoma. Most importantly, the TCA drugs were able to kill SCLC tumors in mice that had become resistant to previous treatment with the chemotherapy drug cisplatin. In addition, the TCA drugs were shown to inhibit growth and kill other human neuroendocrine tumors such as Merkel cell carcinoma, neuroblastoma, and gastrointestinal carcinoid.
On the basis of these findings, Stanford University Cancer Institute has opened a phase IIa clinical trial (NCT01719861) with the TCA drug desipramine. This trial is recruiting SCLC patients, as well as patients with other neuroendocrine tumors who have received at least one line of chemotherapy and have experienced disease progression. The results of the study will only be known a few years down the road, but the discovery of a promising new target in SCLC and the quick transition from a research lab to clinical trials are very exciting. Now, the only thing is to hope that the old antidepressants will work as well in human patients as they did in mice with SCLC.
Cardnell RJ, Feng Y, Diao L, et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res. Published online ahead of print October 23, 2013
Jahchan NS, Dudley JT, Mazur PK, et al. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov. Published online ahead of print September 26, 2013