Lung cancer is the leading cause of cancer death for both men and women in the US. In 2007 alone, over 160,000 patients will succumb to lung cancer, more than the combined deaths from the breast, prostate, and colorectal cancers (ACS, US Cancer Statistics, 2007). Despite a recent downward trend in death rate in the American men, lung cancer death in women and never smokers has continued to grow. Worldwide, the increasing consumption of tobacco products is assuring lung cancer epidemic at an alarming scale within the next decade. Existing strategies for lung cancer interventions have only marginally improved survival over the past several decades. Thus, understanding the mechanisms of lung cancer development and devising novel therapies constitute major challenges in lung cancer research today.

Lung cancers result from cumulative genetic damages to a cell’s DNA. It is estimated that up to 10 such damages are required to convert a normal human lung cell to a malignant one. These damages have two general consequences. One is “turning on” of an oncogene, or tumor-promoting genes; another is the “turning off” of tumor suppressor genes that normally prevent tumor development. Recent studies from my laboratory have identified a novel tumor suppressor gene called EphA2. Interestingly, mice lacking this gene are much more prone to carcinogen-induced lung tumor development.

In both human and mouse lung cancer cells, EphA2 is present at high levels, but the tumor suppressor activity of EphA2 has been “silenced” during tumor development. Excitingly, the tumor suppressor function of the “silenced” EphA2 can be reawakened by administering its missing partners to cancer cells. The treatment is sufficient to inhibit lung cancer cell growth in test tubes. Based on these studies, we hypothesize that the innate tumor suppressor function of EphA2 can be harnessed for lung cancer therapy.  The goal of this proposal is to test this hypothesis in preclinical model systems in mice. Another goal is to find out which other mutated genes can work together with the “silencing” of EphA2 to promote lung cancer. The latter studies can instruct us on what types of lung cancers can be treated with the EphA2-targeted agents, and what other drugs can be used in combination with EphA2-targeted agents for better therapeutic efficacies.

Targeting the innate tumor suppressor function is an emerging new paradigm for cancer therapy, and makes perfect sense. Largely due to the functions of tumor suppressor genes, on average only less than one cell will ever become a tumor in the lifespan of a human being despite trillions of potential target cells. The product of EphA2 tumor suppressor gene is an attractive target because it is present at high levels on human lung cancer cells, and because its tumor suppressor functions can readily re-activated to unleash its anti-tumorigenic functions.