Targeting Notch3 in Lung Cancer

靶向肺癌中的 Notch3

• 批准号: 7322125
• 负责人: Thao P. Dang
• 金额: $ 26.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322125
• 关键词: Acute leukemia; Adult; Apoptosis; Biochemical; Cancer Model; Cancer cell line; Cells; Cessation of life; Clara cell; Clinic; Complex; Data; Development; Disease; Distant Metastasis; Dominant Negative Receptor; Doxycycline; Epithelial Cells; Epithelium; Family; Genes; Genetic Transcription; Growth; Growth Factor; Human; Implant; In Vitro; Induction of Apoptosis; Intervention; Kaposi Sarcoma; Ligands; Link; Lung; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mus; Mutation; Neoplasm Metastasis; Neoplastic Cell Transformation; Neuroblastoma; Normal Cell; Notch Signaling Pathway; Nude Mice; Oncogenic; Organism; Pathogenesis; Pathway interactions; Phenotype; Play; Process; Protein Overexpression; Proteins; Proteolytic Processing; Rate; Research; Research Personnel; Resected; Role; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Therapeutic Intervention; Tissues; Trans-Activators; Transgenic Organisms; Tumor Cell Line; Tyrosine Kinase Inhibitor; Whole Organism; Work; base; carcinogenesis; defined contribution; gamma secretase; in vivo; inhibitor/antagonist; insight; leukemia; lung maturation; lung tumorigenesis; malignant breast neoplasm; member; metaplastic cell transformation; mortality; mouse model; neoplastic cell; notch protein; presenilin; prevent; programs; promoter; protein activation; receptor; respiratory; secretase; trait; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis

Genes that are crucial in the normal development of multi-cellular organisms often play a role in oncogenesis when aberrantly expressed in adult tissues. The Notch signaling pathway is crucial in the cell fate determination, and there is strong evidence demonstrating a role for Notch dysregulation in tumor development. Despite the increasing role of Notch pathway in human cancers, very little was known about the role of NotchS in lung cancers. Our group was the first to link Notch3 pathway with lung cancers. We demonstrated that about 40% of resected lung tumors overexpresses NotchS. In the developing lung, constitutively activated NotchS prevents maturation of lung epithelium. Furthermore, inhibiting the NotchS reduces tumor phenotype, induces apoptosis and renders the tumor cells more dependent of exogenous growth factors. Finally, pharmacologic inhibition of Notch activation reduces proliferation of lung cancer in vitro. Based on our preliminary data, we hypothesize that the NotchS signaling pathway plays a role in the pathogenesis of lung cancer and represents a potential target for intervention. To test these hypotheses, (1) we will examine whether NotchS is sufficient for cellular transformation in vivo using an inducible, Clara cell-driven NotchS expressing mouse model. (2) While transformation is an important aspect in cancer pathogenesis, understanding whether NotchS is important in progression is also important. We will examine the effect of inhibiting NotchS on tumor survival, progression and metastasis in established tumor using an orthotopic lung cancer model. (3) Gamma-secretase is a presenillin-containing protein complex necessary for proteolytic cleavage and activation of Notch receptors. In this aim,we propose to examine the phenotypic and biochemical effects of y-secretase inhibitors on tumor xenografts and to determine the degree to which the anti-tumor effect is Notch-related. These proposed studies will potentially identify NotchS as a target for intervention and provide insights into the mechanism of NotchS-related lung cancer pathogenesis.

对多细胞生物正常发育至关重要的基因通常在 当在成人组织中异常表达时发生肿瘤。 Notch 信号通路在 细胞命运决定，并且有强有力的证据表明 Notch 失调在 肿瘤的发展。尽管Notch通路在人类癌症中的作用越来越大，但人们对它的研究却很少。 已知 NotchS 在肺癌中的作用。我们的小组是第一个将 Notch3 通路与 肺癌。我们证明约 40% 的切除肺肿瘤过度表达 NotchS。在 在肺发育过程中，组成型激活的 NotchS 会阻止肺上皮的成熟。此外， 抑制NotchS可降低肿瘤表型，诱导细胞凋亡并使肿瘤细胞更加活跃 依赖于外源生长因子。最后，Notch 激活的药理抑制可减少 肺癌体外增殖。根据我们的初步数据，我们假设 NotchS 信号通路在肺癌的发病机制中发挥着重要作用，是治疗肺癌的潜在靶点。 干涉。为了检验这些假设，（1）我们将检查 NotchS 是否足以用于细胞 使用可诱导的、Clara 细胞驱动的表达 NotchS 的小鼠模型进行体内转化。 (2) 同时 转化是癌症发病机制的一个重要方面，了解NotchS是否是 进展中的重要也很重要。我们将检查抑制NotchS对肿瘤的影响 使用原位肺癌模型确定已建立肿瘤的生存、进展和转移。 (3) γ-分泌酶是一种含有早老素的蛋白质复合物，是蛋白水解和裂解所必需的。 Notch受体的激活。为此，我们建议检查表型和生化 γ-分泌酶抑制剂对肿瘤异种移植物的影响并确定抗肿瘤的程度 效果与Notch相关。这些拟议的研究将有可能将 NotchS 确定为 干预并为NotchS相关肺癌发病机制提供见解。