Researchers at UCLA’s Jonsson Center, led by Dr. Steven Dubinett, have discovered biomarkers capable of predicting the response to a combination treatment by Celebrex and Tarceva by patients with advanced non-small cell lung cancer.
It is believed that these findings may help oncologists avoid prescribing conventional treatments that don’t work, in favor of drugs to which they know patients will respond.
In 2008 more than 213,000 Americans will be diagnosed with lung cancer, and of these some 160,000 will die. If further studies confirm the findings of this first study, said Dr. Steven Dubinett, a professor of pulmonary and critical care medicine and senior author, this personalized drug therapy would offer a much-needed alternative therapy. "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," he said.
The Phase 1 dose-escalation study of the drug combination surveyed a group of patients for whom all other treatments had been unsuccessful. The tumors in 50% of the patients decreased by more than 30%, or had tumors that did not grow—described as stable disease.
When the UCLA team analyzed tumor, blood and urine samples to find out why some patients did so well, they found several biomarkers that could help identify patients likely to respond to the combination Celebrex and Tarceva therapy. The answer appeared to be in the levels of certain proteins in the patients’ blood: Dubinett said that changes in these proteins may help explain the potential benefit of Celebrex in making the tumor cells more vulnerable to Tarceva.
Cycloxygenase-2 (COX-2) is an enzyme that makes cancer cells resistant to death, and causes resistance to drugs like Tarceva, allowing the cancer to grow.
Dr. Dubinett and his team found that if they inhibited the COX-2 pathway, they could restore the sensitivity of lung cancer tumor cells to Tarceva. The samples from Phase 1 patients showed that patients with low levels of MMP9 before treatment responded best to the combination therapy.
If these findings are confirmed in larger studies, in the future that protein biomarker could be used to place patients into groups with patients having low blood levels of MMP9 receiving the Celebrex and Tarceva therapy and responding. A larger, multi-site Phase 11 study of 10 patients is now under way, to confirm if there is a connection between tumors that express the proteins named in the Phase 1 study and a response to combination treatment.
"This study cold determine whether these biomarkers can be used in the future before treatment to select the patients likely to respond," said Dr. Dubinett.
The findings of the study were published in the February 1, 2008 issue of the Journal of Thoracic Oncology.
Source: University of California Los Angeles (UCLA), Health Sciences