Lung cancer is the leading cause of cancer death worldwide and accounts for more deaths annually in the U.S. than breast, colon, and prostate cancer combined. Approximately 90% of lung cancer patients die of the disease, which is attributed mainly to the advanced stage of the disease at diagnosis and resistance of tumors to current therapies. To improve patient survivorship of lung cancer we wish to identify novel clinical markers to better guide drug treatments and to predict outcome.

Recently, we identified a new gene that inhibits the development of lung cancer. This gene, FOXO3a, is defective in at least 50% of lung adenocarcinomas, indicating that its inactivation is a major factor in the development of these tumors. Evidence, including our unpublished results, suggests that the same functions that make FOXO3a a suppressor of lung cancer also control the processes by which many lung cancer drugs kill cancer cells. As a component of treatment response, its genetic status in lung tumors may then be an important predictor of treatment outcome. While it is evident that some lung cancer patients respond well to current treatments, unfortunately the majority of patients do not. Therefore, genetic predictors of treatment efficacy are needed to identify individuals who will and will not respond to specific treatments. This will identify drug-resistant tumors that require different or more aggressive treatment regimens, as well as reduce patient exposure to ineffective and unnecessary treatments. A major goal of this proposal is to determine whether FOXO3a gene status in lung tumors predicts response to currently used treatments. Towards this goal we will test different human lung cancer cell lines for their susceptibility to drug treatments and determine the role of FOXO3a in the tumor response to these drugs.

Because of FOXO3a’s frequent inactivation in lung cancer, a critical component necessary for the therapeutic killing of cancer cells may be absent. Importantly, FOXO3a is a transcription factor that controls the expression of many genes, some of which are expected to be critical in therapeutic-induced tumor cell killing. Those genes regulated by FOXO3a that are critical for this role are themselves potential targets of lung cancer. A second major goal of this proposal therefore is to identify genes regulated by FOXO3a that execute cell death in response to current treatments as these represent potential improvements in treatment efficacy and patient survivorship.