ErbB1 signaling and cancer-mediated diseases of bone

ErbB1 信号传导和癌症介导的骨疾病

• 批准号: 6923035
• 负责人: JOHN Gregory FOLEY
• 金额: $ 15.15万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923035
• 关键词: autocrine; biological signal transduction; bone disorder; enzyme inhibitors; epidermal growth factor; gene expression; growth factor receptors; hormone related neoplasm /cancer; hypercalcemia; laboratory mouse; lung neoplasms; parathyroid hormone related protein; second messengers; squamous cell carcinoma

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.

描述（由申请人提供）：在美国，肺癌每年导致超过 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%）新病例将是一种称为鳞状细胞癌的疾病，其中（约 90%）似乎是吸烟造成的。美国吸烟率持续居高不下，加上这种疾病的五年生存率仅为 14%，表明迫切需要改进治疗方法。此外，鳞状细胞癌对骨骼具有破坏性影响。大部分患有这种肿瘤的患者患有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。该综合征是由于肿瘤衍生的甲状旁腺激素相关蛋白（PTHrP）释放到循环中引起的，然后影响肾脏和骨骼中的甲状旁腺激素靶标，导致血清钙水平升高。该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（一种刺激骨质破坏的分子）的界面，以利用最近开发的针对表皮生长因子的疗法来治疗高钙血症。 我实验室的最新证据表明，培养的正常细胞中 PTHrP 基因的高水平表达依赖于上皮生长因子受体信号传导。绝大多数肺部鳞状细胞癌产生激活该受体的配体，这表明了以下假设。 肺鳞状细胞癌中 erbB1 受体信号的自分泌激活会激活高水平的 PTHrP 基因表达，从而导致高钙血症。 具体目标 1：确定 erbB1 信号传导刺激肺鳞状细胞癌细胞系中的 PTHrP 基因表达。 在这些实验中，我们将使用三种肺 SCC 系，当异种移植到裸鼠中时，它们会导致高钙血症。最初，我们将表征这些细胞系中的 erbB1 信号系统，并确定该受体是否激活 PTHrP 基因表达。接下来，erbB1酪氨酸激酶抑制剂PD153035和ZD1839（易瑞沙）将被用于尝试在体外降低PTHrP基因表达。随后，这些化合物将用于确定介导 erbB1 对 PTHrP 基因表达影响的特定第二信使途径。最后，我们将确定 erbB1 信号传导是否在转录或信息稳定性水平上调节 PTHrP 基因表达。 具体目标 2. 使用 erB1 抑制剂治疗异种移植模型中的高钙血症。 我们将使用两种治疗方案来确定 ZD1839 是否可以逆转由三种 SCC 系诱导的高钙血症。第一个将涉及使用高剂量 ZD1839 来急性逆转由大肿瘤引起的高钙血症。第二个项目将在肿瘤的整个生长阶段使用较低剂量的 ZD1839 治疗，以确定阻断该途径是否可以防止高钙血症的发生。