Bingcheng Wang Ph.D.

Lay Description

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, models lacking this gene are much more prone to carcinogen-induced lung tumor development.

In both human and model 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. 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.

Scientific Abstract

EphA2 receptor tyrosine kinase is frequently overexpressed in various human cancers, leading to the suggestion that it may be an oncoprotein. Surprisingly, recent studies from the applicant’s laboratory show that EphA2 is a novel tumor suppressor gene in mammalian lung, and is an attractive target for lung cancer therapy. Multiple lines of evidence support this notion: 1) EphA2 homozygous knockout mice but not their wild type littermates displayed markedly increased susceptibility to chemically induced lung carcinogenesis. 2) Intriguingly, unlike conventional tumor suppressor genes that are lost or mutated in tumors, EphA2 was consistently upregulated in tumors arising in wild type mice. The overexpression is robust and occurs very early, even in preneoplastic lesions. 3) However, the overexpressed EphA2 is poorly activated in mouse tumors in vivo and human NSCLC cells in vitro, suggesting that tumor suppressor activities of EphA2 have been functionally silenced during tumorigenesis. 4) In human NSCLC cells in vitro, the latent tumor suppressor function of EphA2 can be reawakened by stimulation with ephrin-A1, a ligand for EphA2, and caused suppression of ERK1/2 and Akt kinase activities and inhibition of cell migration and proliferation. Forced expression of EphA2 on lung cancer cells sensitized cells to growth inhibition by rapamycin, and cotreatment with ephrin-A1 had cooperative inhibitory effects. 5) More importantly, we have demonstrated that systemic administration of ephrin-A1-Fc led to selective homing of the ligand to tumors that overexpress the dormant EphA2, and activated it.

The overarching goal of this proposal is to uncover the molecular mechanisms of the tumor suppressor function of EphA2 kinase in mammalian lung, and to test if the intrinsic tumor suppressor activities of EphA2 kinase can be harnessed for lung cancer therapy. Aim 1 will test the effects of EphA2 deletion on lung oncogenesis induced by mutant K-Ras and p53. In Aim 2, ephrin-A1 will be systemically administered to test its therapeutic efficacy against lung tumors by itself or in combination with other agents including rapamycin and conventional cytotoxic drugs. The proposed studies will lead to the characterization of a novel lung tumor suppressor gene, and an innovative paradigm of exploiting innate tumor suppressor function of EphA2 kinase for therapeutic intervention of lung cancer.