Targeting Notch3 in Lung Cancer

靶向肺癌中的 Notch3

• 批准号: 7211838
• 负责人: Thao P. Dang
• 金额: $ 26.2万
• 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/7211838
• 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

DESCRIPTION (provided by applicant): 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 Notch3 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 Notch3. In the developing lung, constitutively activated Notch3 prevents maturation of lung epithelium. Furthermore, inhibiting the Notch3 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 Notch3 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 Notch3 is sufficient for cellular transformation in vivo using an inducible, Clara cell-driven Notch3 expressing mouse model. (2) While transformation is an important aspect in cancer pathogenesis, understanding whether Notch3 is important in progression is also important. We will examine the effect of inhibiting Notch3 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 Notch3 as a target for intervention and provide insights into the mechanism of Notch3-related lung cancer pathogenesis.

描述（由申请人提供）：对于多细胞生物正常发育至关重要的基因，当在成体组织中异常表达时，通常在肿瘤发生中发挥作用。 Notch 信号通路在细胞命运决定中至关重要，并且有强有力的证据表明 Notch 失调在肿瘤发展中发挥作用。尽管Notch通路在人类癌症中的作用越来越大，但人们对Notch3在肺癌中的作用知之甚少。我们的团队是第一个将 Notch3 通路与肺癌联系起来的团队。我们证明约 40% 的切除肺肿瘤过度表达 Notch3。在发育中的肺中，组成型激活的 Notch3 会阻止肺上皮的成熟。此外，抑制Notch3可降低肿瘤表型，诱导细胞凋亡，并使肿瘤细胞更加依赖于外源生长因子。最后，Notch 激活的药理抑制可减少体外肺癌的增殖。根据我们的初步数据，我们假设Notch3信号通路在肺癌的发病机制中发挥作用，并代表了潜在的干预靶点。为了检验这些假设，(1) 我们将使用可诱导的、Clara 细胞驱动的表达 Notch3 的小鼠模型来检查 Notch3 是否足以进行体内细胞转化。 (2) 虽然转化是癌症发病机制的一个重要方面，但了解 Notch3 在进展中是否重要也很重要。我们将使用原位肺癌模型检查抑制 Notch3 对已建立肿瘤的肿瘤存活、进展和转移的影响。 (3) γ-分泌酶是一种含有早老素的蛋白质复合物，是蛋白水解裂解和Notch受体激活所必需的。为此，我们建议检查γ-分泌酶抑制剂对肿瘤异种移植物的表型和生化作用，并确定抗肿瘤作用与Notch相关的程度。这些拟议的研究将有可能将 Notch3 确定为干预靶点，并提供对 Notch3 相关肺癌发病机制的见解。