ErbB1 signaling and cancer-mediated diseases of bone

描述（由申请人提供）：肺癌在美国每年导致超过154,000人死亡，是迄今为止工业世界中最致命的癌症。超过57,000例（占总数的38%）的新病例将是一种叫做鳞状细胞癌的疾病，其中（约90%）似乎是吸烟的后果。美国持续的高吸烟率，加上这种疾病的5年生存率仅为14%，表明对改进治疗的巨大需求。此外，鳞状细胞癌对骨骼有毁灭性的影响。该肿瘤的大部分患者表现为恶性相关的高钙血症。高钙血症是一种危及生命的疾病，患者会出现一系列神经系统疾病、呕吐、急性胰腺炎、心律失常和肾功能受损。这种综合征是由肿瘤衍生的甲状旁腺激素相关蛋白（PTHrP）释放到血液循环中引起的，然后影响肾脏和骨骼中的甲状旁腺激素靶点，导致血清钙水平升高。本提案将研究肺癌中表皮生长因子受体（一种生长刺激途径）和PTHrP（一种刺激骨骼破坏的分子）的界面，努力使用最近开发的靶向表皮生长因子治疗高钙血症的治疗方法。

DESCRIPTION (provided by applicant): 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.