Targeting Notch3 in Lung Cancer

描述(申请人提供)：在多细胞生物体的正常发育中至关重要的基因，当在成人组织中异常表达时，通常在肿瘤发生中发挥作用。Notch信号通路在细胞命运的决定中至关重要，有强有力的证据表明Notch失调在肿瘤发展中起着作用。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。我们小组是第一个将Notch3通路与肺癌联系起来的小组。我们证明了大约40%的切除的肺肿瘤过度表达Notch3。在发育中的肺中，结构性激活的Notch3阻止了肺上皮的成熟。此外，抑制Notch3减少肿瘤表型，诱导细胞凋亡，使肿瘤细胞对外源生长因子的依赖性更强。最后，药物抑制Notch激活可减少肺癌细胞的体外增殖。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了作用，并代表了一个潜在的干预靶点。为了验证这些假设，(1)我们将使用可诱导的Clara细胞驱动的Notch3表达小鼠模型来检验Notch3是否足以在体内进行细胞转化。(2)虽然转化是癌症发病机制中的一个重要方面，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来研究抑制Notch3对已建立的肿瘤的生存、进展和转移的影响。(3)γ-分泌酶是一种含早老素的蛋白质复合体，对Notch受体的蛋白水解性切割和激活是必需的。为此，我们建议检测Y-分泌酶抑制剂对肿瘤移植瘤的表型和生化效应，并确定抗肿瘤效应与Notch相关的程度。这些拟议的研究可能会确定Notch3作为干预的目标，并为Notch3相关肺癌的发病机制提供见解。

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.