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ErbB1 signaling and cancer-mediated diseases of bone

ErbB1 信号传导和癌症介导的骨疾病

基本信息

批准号：
7054717
负责人：
JOHN Gregory FOLEY
金额：
$ 14.79万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/7054717
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

项目摘要

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）：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形式。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%）似乎是吸烟的结果。在美国，吸烟率持续高企，再加上这种疾病的五年生存率仅为14%，这表明非常需要改进治疗方法。此外，鳞状细胞癌对骨具有破坏性影响。大部分患有这种肿瘤的患者表现为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。这种综合征是由肿瘤源性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点，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（一种刺激骨破坏的分子）的界面，以使用最近开发的靶向表皮生长因子的治疗方法来治疗高钙血症。最近的证据表明，PTHrP基因在培养的正常细胞中的高水平表达依赖于上皮生长因子受体信号传导。肺的绝大多数SCC产生激活该受体的配体，表明以下假设。肺鳞状细胞癌中erbB1受体信号的自分泌激活激活PTHrP基因的高水平表达，从而导致高钙血症。具体目的1：建立erbB1信号刺激肺鳞状细胞癌细胞系PTHrP基因表达。在这些实验中，我们将使用三个肺SCC系，当在裸鼠中异种移植时，其引起高钙血症。最初，我们将在这些线的erbB1信号系统的特点，并确定该受体激活PTHrP基因的表达。接下来，将使用erbB1酪氨酸激酶抑制剂PD 153035和ZD 1839（易瑞沙）来尝试在体外降低PTHrP基因表达。随后，这些化合物将用于确定介导erbB1对PTHrP基因表达的影响的特定第二信使途径。最后，我们将确定是否erbB1信号调节PTHrP基因的表达在转录水平或信息稳定性。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ZD 1839是否可以逆转三种SCC细胞系诱导的高钙血症。第一个将涉及使用高剂量ZD 1839来急性逆转由大肿瘤引起的高钙血症。第二项研究将在整个肿瘤生长阶段使用较低剂量的ZD 1839治疗，以确定阻断该途径是否可以预防高钙血症的发生。