ErbB1 signaling and cancer-mediated diseases of bone

描述(申请人提供)：在美国，每年有超过15.4万人死于肺癌，是迄今为止工业世界中最致命的癌症。超过57,000个新病例(占总数的38%)将是一种被称为鳞状细胞癌的疾病，其中(约90%)似乎是由吸烟引起的。美国的吸烟率持续居高不下，加上这种疾病的五年存活率只有14%，这表明非常需要改进治疗方法。此外，鳞状细胞癌对骨骼有毁灭性的影响。这种肿瘤的很大一部分患者存在与恶性肿瘤相关的高钙血症。高钙血症是一种危及生命的疾病，患者患有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。这种综合征是由于肿瘤来源的甲状旁腺激素相关蛋白(PTHrP)释放到循环中，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。这项建议将研究肺癌中表皮生长因子受体(一种生长刺激途径)和甲状旁腺素受体(一种刺激骨骼破坏的分子)的界面，以努力使用最近开发的针对表皮生长因子的疗法来治疗高钙血症。 最近来自我的实验室的证据表明，培养的正常细胞中高水平的PTHrP基因表达依赖于上皮生长因子受体信号。绝大多数肺的干细胞会产生激活该受体的配体，这就提出了以下假设。 肺鳞癌中ErbB1受体信号的自分泌激活激活了高水平的PTHrP基因表达，从而导致高钙血症。 具体目的1：建立ErbB1信号对肺鳞癌PTHrP基因表达的刺激作用。 在这些实验中，我们将使用三个肺鳞状细胞癌株，它们在裸鼠体内异种移植时会导致高钙血症。首先，我们将确定这些细胞系中ErbB1信号系统的特征，并确定该受体是否激活PTHrP基因的表达。接下来，ErbB1酪氨酸激酶抑制剂PD153035和ZD1839(易瑞沙)将被用来试图在体外降低PTHrP基因的表达。随后，这些化合物将被用来确定介导ErbB1对PTHrP基因表达的影响的特定第二信使途径。最后，我们将确定ErbB1信号是否在转录水平或消息稳定水平上调节PTHrP基因的表达。 具体目的2.使用erB1抑制剂治疗异种移植模型中的高钙血症。 我们将使用这两种治疗方案来确定ZD1839是否能逆转三种鳞状细胞癌株所致的高钙血症。第一项将涉及使用高剂量的ZD1839来迅速逆转由大肿瘤引起的高钙血症。第二项研究将在肿瘤的整个生长阶段使用较低剂量的ZD1839治疗，以确定阻断这一途径是否可以防止高钙血症的发展。

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.