Researchers have discovered biomarkers that predict which patients with advanced non-small cell lung cancer will respond to the combination of celecoxib and erlotinib, according to an article in the February 1 issue of the Journal of Thoracic Oncology.

The work was done at the Jonsson Cancer Center of the University of California at Los Angeles.

If the findings are confirmed in further studies, the personalized drug combination would offer an alternative therapy in a disease population in which new, more effective treatments are needed, said Doctor Steven Dubinett, a professor of pulmonary and critical care medicine and senior author of the study. This year alone, more than 213,000 Americans will be diagnosed with lung cancer. Of those, more than 160,000 will die.

"We need good predictors of response to targeted therapy in lung cancer so individual patients receive the specific therapy that targets the particular molecular abnormalities of their tumors," said Dubinett, who also serves as director of the cancer center's Specialized Program of Research Excellence (SPORE) in lung cancer.

The findings grew out of a Phase I dose-escalation study of the drug combination in a small group of patients who had failed all other treatment options. The early phase study resulted in more patient responses than expected in people with advanced lung cancer.

About 50 percent of patients had a decrease in tumor size of more than 30 percent or had stable disease.

The researchers studied tumor, blood and urine samples to discover why some patients did well and others did not. Their findings identified several biomarkers that could potentially help identify patients likely to respond to the combination therapy and those who were not likely to respond.

Researchers found higher levels of certain proteins in the blood of patients who did not respond to therapy. Other proteins were found that declined in level in patients who responded to treatment. Dubinett said that changes in these protein levels may help explain the potential benefit of celecoxib in rendering the tumor cells more vulnerable to erlotinib.

About 80 to 85 percent of lung tumors overexpress cycloxygenase-2 (COX-2). Enzyme activity appears to cause resistance to drugs like erlotinib that inhibit epidermal growth factor receptors.

Only about 15 percent of lung cancer patients respond to erlotinib and they later become resistant. The researchers found that if they inhibited the COX-2 pathway, they were able to restore the sensitivity of lung cancer tumor cells to erlotinib.

That finding led to the Phase I study of the combination therapy. In analyzing samples from the Phase I patients, the research team found that patients with low levels of MMP9 before treatment had the best response to the combination therapy. That protein biomarker might be used one day to stratify patients into groups. If these results are confirmed in larger studies, patients with low blood levels of MMP9 could receive the combination and expect to respond.

The work is now being tested in a much larger, multi-site Phase II study of 100 patients. The samples taken from patients at all study sites - before and after treatment - will be analyzed in Jonsson Cancer Center laboratories. Investigators will seek to confirm whether there's a connection between tumors that express the proteins identified in the Phase I study and a response to the combination therapy.

This larger study could provide evidence that effective combination targeted therapies for lung cancer can be developed in the near future and provided to patients whose blood tests suggest they are most likely to benefit. It also could determine why all lung cancers don't respond to the same treatment and promote a personalized medicine approach that would group patients by the molecular signatures found in their tumors and bloodstream rather than by cancer type.

"This study could determine whether these biomarkers can be used in the future before treatment to select the patients likely to respond," said Dubinett.