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.
However, some promising new SCLC treatment options have just recently emerged from laboratory research and are already being explored in clinical trials. One is a targeted therapy using a drug that inhibits the cellular enzyme PARP1. PARP1 inhibitors are already being investigated in clinical trials for other cancers, though FDA approvals for these drugs are still pending. In late September of this year, investigators at MD Anderson Cancer Center in Houston, Texas, published a study that describes a remarkable sensitivity of SCLC to the novel PARP1 inhibitor BMN-673.
PARP1 is a cellular protein that has a major function in detecting and initiating the repair of DNA damage. DNA damage is an ongoing process most cells have to deal with, but many cancer cells tend to accumulate more DNA damage than normal cells. This could be due to certain metabolic processes preferred by cancer cells. The lack of cellular ability to repair damage to DNA usually has serious consequences, from disruption of cell doubling, to cell death if the DNA damage is too severe. Therefore, drugs that inhibit PARP have the potential to preferentially hit cancer cells. Several such drugs have been developed and are in clinical trials.
The researchers from MD Anderson Cancer Center identified high levels of PARP1 in SCLC cells in earlier studies. Now they have examined the effects of PARP inhibitors on SCLC cells and have found that BMN-673 kills SCLC cells grown in the laboratory more efficiently than an older PARP inhibitor called olaparib. SCLC tumors grown in mice were also remarkably sensitive to treatment with BMN-673. Additionally, the study examined which biomarkers could predict the response of SCLC to BMN-673 and found that high levels of PARP and other proteins involved in DNA damage repair are strongly associated with the sensitivity of SCLC cells to BMN-673. These biomarkers (and others discovered in the study) could hopefully be incorporated into future clinical studies of this drug.
BMN-673 entered clinical testing only recently, but it had already been reported to have excellent activity in breast and ovarian cancer at the American Society for Clinical Oncology meeting in spring of 2013. Based on the preclinical data described above, a cohort of SCLC patients is being enrolled in phase I study NCT01286987 to determine the maximum tolerated dose of BMN-673. The study is being conducted in several medical centers in the U.S. and UK and is sponsored by the drug manufacturer BioMarin Pharmaceutical.
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