Lung cancer kills over 154,000 people a year in the US and is by far the most deadly form of cancer in the industrial world. Over 57,000 (38% of the total) new cases will be a form of the disease called squamous cell carcinoma of which (approximately 90%) appear to be a consequence of smoking. The continued high smoking rates in the US coupled with the fact that the five-year survival rate for this disease is only 14%, indicate a great need for improved therapies. In addition, squamous cell carcinomas have a devastating impact upon bone. A large fraction of patients with this tumor present with malignancy-associated hypercalcemia. Hypercalcemia is a life-threatening disorder where patients suffer from a spectrum of neurological disorders, vomiting, acute pancreatitis, cardiac arrhythmias and impaired kidney function. This syndrome is caused by the release of tumor derived-parathyroid hormone-related protein (PTHrP) into the circulation, which then affects the parathyroid homone targets in kidney and bone, resulting in high serum calcium levels. This proposal will study the interface of the epidermal growth factor receptor (a growth stimulating pathway) and PTHrP (a molecule that stimulates bone destruction) in lung cancer in an effort to use recently developed therapeutics that target the epidermal growth factor to treat hypercalcemia. Recent evidence from my lab suggests that high levels of PTHrP gene expression in cultured normal cells is dependent on of the epithelial growth factor receptor signaling. The vast majority of SCCs of the lung produce ligands that activate this receptor, suggesting the following hypothesis. Autocrine activation of the erbB1 receptor signaling in squamous carcinomas of the lung activates high levels of PTHrP gene expression, which leads to hypercalcemia.
Specific Aim 1 : Establish that erbB1 signaling stimulates PTHrP gene expression in a lung squamous cell carcinoma lines. We will use three lung SCC lines which causes hypercalcemia when xenografted in nude mice in these experiments. Initially we will characterize the erbB1 signaling system in these lines and determine if this receptor activates PTHrP gene expression. Next, erbB1 tyrosine kinase inhibitors PD153035 and ZD1839 (Iressa) will be used in an attempt to decrease PTHrP gene expression in vitro. Subsequently, these compounds will be used to determine the specific second messenger pathway that mediates the effects if erbB1 on PTHrP gene expression. Finally we will determine if erbB1 signaling regulates PTHrP gene expression at the level of transcription or message stability.
Specific Aim 2. Use of erB1 inhibitors to treat hypercalcemia in xenograft models. We will use the two treatment regimens to determine if ZD1839 can reverse hypercalcemia induced by three SCC lines. The first will involve the use of high doses ZD1839 to acutely reverse hypercalcemia caused by large tumors. The second will use lower dose treatments of ZD1839 through out the growth phase of the tumor to determine if blockade of this pathway could prevent the development of hypercalcemia.
| Gilmore, Jennifer L; Gonterman, Ryan M; Menon, Keshav et al. (2009) Reconstitution of amphiregulin-epidermal growth factor receptor signaling in lung squamous cell carcinomas activates PTHrP gene expression and contributes to cancer-mediated diseases of the bone. Mol Cancer Res 7:1714-28 |
| Wilson, Kristy J; Gilmore, Jennifer L; Foley, John et al. (2009) Functional selectivity of EGF family peptide growth factors: implications for cancer. Pharmacol Ther 122:1-8 |
| Gilmore, Jennifer L; Scott, Jeffrey A; Bouizar, Zhor et al. (2008) Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells. Breast Cancer Res Treat 110:493-505 |
| Lorch, G; Gilmore, J L; Koltz, P F et al. (2007) Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice. Br J Cancer 97:183-93 |
