Repression of c-Jun oncogene activity in lung cancer
Initial Award Abstract
It is estimated that lung cancer led to 1.3 million deaths worldwide in 2007, contributing to 15% of all cancer deaths. Smoking is the leading origin of lung cancer worldwide, causing 80% of the disease in men and 50% in women. In the year 2008, there is an anticipated 215,020 new cases of lung cancer in the United States, with 18,060 in California alone, leading to a corresponding 13,100 deaths in the state. Non-small cell lung cancer (NSCLC) contributes to 80% of all lung cancer cases, and tobacco smoking is its leading cause. The development of more effective treatments for NSCLC is therefore greatly needed.
A signature attribute of NSCLC is the over-expression of the c-jun oncogene, which encodes the c-Jun protein. Analysis of tumor specimens revealed that 31-50% of patients with NSCLC also possessed elevated c-jun expression levels. The c-Jun protein regulates the gene expression of other proteins by combining with another protein (c-Fos) and recognizing specific DNA sequences. When c-Jun is over-expressed, many of these c-Jun-regulated genes also become deregulated and frequently lead to uncontrolled cell cycle progression, a trademark of cancer.
In our proposed research, we hope to disrupt the c-Jun/c-Fos units from binding to those specific DNA sequences that cause the deregulation of other genes. By blocking this event, we believe that the NSCLC cells will be unable to continue growth and lead to cell death. A small molecule will be designed to bind specifically to these desired DNA sites and literally block them from the protein. This approach does not perturb the production of c-Jun protein, but only aims at disrupting its proto-oncogenic activity. We believe that this is significant because c-Jun also functions via different pathways for normal cellular functions. Our plan is to generate a set of DNA-binding molecules and examine their abilities to disrupt deregulated c-Jun activity, and their potential as anti-cancer reagents. If we should succeed, this research may form the foundation for new human cancer treatment methods. |