Edwina C. Lerner Ph.D.

Lay Description

Lung cancer, rare in women in the early 1900s has reached epidemic proportions accounting for nearly 29% of all cancer deaths in females in the United States. Although lung tumors are classified into many different subtypes, the predominant risk factor for all tumor types is cigarette smoking. However, bronchioalveolar carcinoma (BAC), a unique subtype of non-small cell lung cancer (NSCLC), is increasing in incidence, and it is most prevalent in females who have never smoked. Unfortunately, no optimal therapy has been established. Oral inhibitors targeting proteins on the cell surface, specifically the epidermal growth factor receptor (EGFR), have proven to be ineffective as the sole chemotherapy agent, resulting in regrowth of the tumor and death of the patient. Only those lung tumors that contain a specific mutation in the EGFR are sensitive to drugs, such as gefitinib or erlotinib. Emerging evidence indicates that the relative risk of BAC between men and women and the response to therapy may not be the same. One type of molecule expressed on the cell that activates growth pathways in the lung is the gastrin releasing peptide receptor (GRPR). These receptors have a role in normal lung development, but also stimulate cells to grow enabling tumor formation. The gene for GRPR is located on the X-chromosome, the chromosome that designates the female sex (XX chromosomes), allowing for women to have two actively transcribed copies of the gene, while men (XY chromosomes) have only one active copy. Our laboratory has shown that GRPR expression is greater in nonsmoking females than nonsmoking males (55% vs 0%). More recent unpublished data shows that activation of the GRPR pathway causes the release of molecules that can activate EGFR, causing this pathway to continue to produce growth signals despite the presence of a specific inhibitor. We have created a preclinical model in which the human gene for GRPR is expressed in the airway epithelial cells that may give rise to BAC. Initial studies show that these models have an increased growth in their airway cells and an increased susceptibility to lung cancer when treated with a tobacco carcinogen. We propose to test the effects of GRPR antagonists alone or in combination with EGFR inhibitors to demonstrate that inhibiting both pathways is more effective in preventing tumor growth than either one alone. Therefore, this combined mode of treatment may have therapeutic potential in non-smoking females with adenocarcinoma where high GRPR expression is observed.

Scientific Abstract

The epidermal growth factor receptor (EGFR) has been shown to be expressed at a relatively high level in non-small cell lung cancer (NSCLC), and it provides an important target for lung cancer therapy. Blockade of the EGFR by small molecule inhibitors of the tyrosine kinase (TK), such as gefitinib and erlotinib, have shown some limited clinical utility against NSCLC, but response rates have been restricted for the most part to patients having EGFR mutations.

We have evidence that another ligand receptor system, the gastrin releasing peptide receptor (GRPR) pathway, can activate similar cell signals in NSCLC that are also activated by EGFR, due to the release of EGFR ligands such as TGF-? and amphiregulin. The EGFR ligand release appears to induce cell proliferation and protects the cells from the cell-killing effects of EGFR inhibitors. Previous work from our laboratory has shown that expression of GRPR is associated with an increased risk for lung cancer particularly in female non-smokers. The GRPR gene is located on the X-chromosome and escapes X-chromosome inactivation. This occurs only in females, giving further evidence that GRPR may play a role in the increased susceptibility of women to lung cancer by promoting the release of EGFR ligands. Published work from our laboratory has also shown that GRP inhibition in vitro using GRP antagonists can increase the therapeutic effects of gefitinib in NSCLC. Modulation of the GRPR pathway might alter lung tumor growth, especially in BAC or adenocarcinoma with BAC features, which are found predominantly in female patients. In order to evaluate the role of GRPR in lung tumor carcinogenesis and to test the chemotherapeutic potential of combined inhibition of the GRPR and the EGFR pathways, we have made a transgenic model that overexpresses the human GRPR gene in the small airway epithelium. Preliminary data have shown that the GRPR-overexpressing models develop small airway hyperplasia compared to their wild-type littermates, and that they are more susceptible to lung cancer when treated with a tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We will use this in vivo model to determine the susceptibility to lung carcinogenesis and the status of GRPR/EGFR downstream signaling molecules in the transgenic models expressing the human GRPR gene.