Despite advances in treating many cancers, the standard treatment of small cell lung cancer has remained unchanged for decades. But researchers at The University of Texas MD Anderson Cancer Center are exploring several new approaches to treat small cell lung cancer.
The standard treatment for small cell lung cancer has remained largely unchanged since the 1980s. Newly diagnosed patients with disease limited to one region of the chest typically receive radiation therapy with carboplatin and etoposide, while those with more extensive disease receive chemotherapy alone. In most patients, the tumors initially shrink markedly but start growing again in 4–6 months.
The targeted agents that are effective against many types of cancer, including non–small cell lung cancer, are ineffective against small cell lung cancer, said John Heymach, M.D., Ph.D., a professor in and chair of the Department of Thoracic/Head and Neck Medical Oncology. “In non–small cell lung cancer, there’s often a single driver oncogene that we can target with new drugs,” he said. “But small cell lung cancer is wired differently. Small cell lung cancer doesn’t seem to have these driver oncogenes. We think what drives it is the loss of tumor suppressor genes RB1 and TP53.”
To identify new therapeutic targets for small cell lung cancer, researchers led by Lauren Byers, M.D., an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology, conducted a proteomic analysis of both small cell and non–small cell lung cancer cell lines to systematically assess the activation of critical intracellular signaling pathways. “Because there haven’t been any approved targeted drugs for small cell lung cancer, we wanted to identify differences between small cell and non–small cell lung cancer that could help us identify new drugs that could work against small cell lung cancer,” Dr. Byers said.
The researchers found that PARP1, an enzyme involved in DNA repair, was expressed at high levels in small cell lung cancer cells. Dr. Heymach said these high levels may be related to the loss of RB1 and TP53.
The discovery of elevated PARP1 expression in small cell lung cancer was exciting because drugs that inhibit PARP proteins are available; such drugs are sometimes used to treat breast or ovarian cancers in patients with BRCA1 or BRCA2 mutations. “The idea is that since tumors with BRCA mutations already have a defect that inhibits their ability to repair DNA damage, the PARP inhibitor will further impair the cells’ ability to repair DNA damage and cause the cells to die,” Dr. Byers said. When further experiments showed that PARP inhibitors used to treat breast and ovarian cancers also killed small cell lung cancer cells, Dr. Byers said, “We saw the opportunity to take our observation into the clinic quickly.”
Dr. Byers is leading or participating in three ongoing clinical trials of PARP inhibitors for lung cancer treatment—one for non–small cell and two for small cell lung cancer. Currently enrolling patients with relapsed or refractory small cell lung cancer is a multicenter phase II trial of the PARP inhibitor veliparib (previously called ABT-888) with the cytotoxic drug temozolomide. Patients in the study are randomly assigned to receive temozolomide with veliparib or placebo.
The study’s goal is to learn whether the addition of veliparib will extend progression-free survival. “The idea is that the cytotoxic drug causes DNA damage in the cancer cells, and the PARP inhibitor prevents the cancer from repairing the damage,” Dr. Byers said. “It’s still early, but we’re excited by some of the results we’re seeing.”
The second study of PARP inhibitors in small cell lung cancer is a first-in-human study of the PARP inhibitor BMN 673. The goals of this study are to find the maximum tolerated dose of BMN 673 and to assess the drug’s efficacy in patients with advanced or recurrent solid tumors. The trial recently reached its enrollment goal.
Preliminary results of the BMN 673 trial were presented last year at the annual meeting of the American Society of Clinical Oncology. Of 11 evaluable patients with small cell lung cancer, 2 had a complete response according to the Response Evaluation Criteria in Solid Tumors and another 6 had either a partial response or stable disease lasting longer than 8 weeks. “The data were preliminary, but they were encouraging,” Dr. Byers said. “Patients seemed to benefit from the drug in the second-line setting.”
Even as the clinical trials progress, Dr. Byers continues to study small cell lung cancer in the laboratory. Because BRCA mutations have not been linked to small cell lung cancer, Dr. Byers and other researchers believe that PARP inhibitors work differently in small cell lung cancer than in breast and ovarian cancers. “Our lab is trying to find out which characteristics of small cell lung cancer make it particularly sensitive to these targeted drugs,” Dr. Byers said, adding that a biomarker has not yet been found to indicate which patients with small cell lung cancer are most likely to respond to PARP inhibitors. “We want to understand which patients will get the most benefit from these drugs.”
The next step in PARP inhibitor research will be testing the drugs with front-line treatments. Dr. Byers and her colleagues are planning a clinical trial in which the PARP inhibitor veliparib will be given with the standard initial regimen of carboplatin and etoposide plus radiation therapy for patients with extensive stage small cell lung cancer.
Like PARP inhibitors, antiangiogenic drugs have been used effectively against other types of cancer and are now under investigation for the treatment of small cell lung cancer. Dr. Heymach thinks that antiangiogenic drugs such as vascular endothelial growth factor (VEGF) inhibitors may be effective against small cell lung cancer when combined with other agents. A clinical trial of the PARP inhibitor olaparib and the VEGF inhibitor cediranib for the treatment of advanced small cell lung cancer is being developed at MD Anderson.
Another promising avenue of research, still in its early stages, is to engineer T cells using chimeric antigen receptors (see “Sleeping Beauty” Technique Modifies T Cells to Treat B Cell Malignancies, OncoLog, May 2014) so that the T cells recognize small cell lung cancer. MD Anderson researchers including Laurence Cooper, M.D., Ph.D., a professor in the Division of Pediatrics, and Warren Denning, Ph.D., a postdoctoral fellow in the Department of Thoracic/Head and Neck Medical Oncology, are modifying T cells so that they bind to CD56, which is expressed on small cell lung cancer cells.
“We’re also hoping that immunotherapy will be effective against small cell lung cancer, but there aren’t any data yet,” Dr. Heymach said. Among the researchers investigating this approach are James Welsh, M.D., an associate professor in the Department of Radiation Oncology, and Kathryn Gold, M.D., and Erminia Massarelli, M.D., Ph.D., both assistant professors in the Department of Thoracic/Head and Neck Medical Oncology. Dr. Heymach believes that immunotherapy drugs may be most effective after front-line chemoradiation therapy has minimized a patient’s tumor burden. A study is being planned in which patients with advanced small cell lung cancer will receive standard chemoradiation therapy followed by the immunotherapy agent pembrolizumab (also called MK-3475), which targets programmed cell death protein 1.
Dr. Byers hopes that these other avenues of research will progress as rapidly as her group’s PARP research has. “We published the paper of our initial discovery of PARP in small cell lung cancer in 2012. That’s a fast turnaround time for translational medicine, to go from a discovery published in 2012 to clinical results reported in 2014.”
For more information, contact Dr. Lauren Byers at 713-792-6363 or Dr. John Heymach at 713-792-6363. To learn more about ongoing clinical trials at MD Anderson for patients with lung cancer, visit www.clinicaltrials.org and select “view studies by cancer type.”
Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2012;2:798–811.
Wainberg ZA, Rafii S, Ramanathan RK, et al. Safety and antitumor activity of the PARP inhibitor BMN 673 in a phase I trial recruiting metastatic small cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients [ASCO abstract 7522]. J Clin Oncol. 2014;32(suppl):5s.
OncoLog, March 2015, Volume 60, Issue 3