Targeting Notch3 in Lung Cancer

在多细胞生物正常发育中至关重要的基因通常在以下方面发挥作用： 在成体组织中异常表达时的肿瘤发生。Notch信号通路在免疫系统中至关重要 细胞命运的决定，有强有力的证据表明，Notch失调的作用， 肿瘤发展尽管Notch通路在人类癌症中的作用越来越大，但很少有研究表明Notch通路在人类癌症中起作用。 NotchS在肺癌中的作用。我们的团队是第一个将Notch 3途径与 肺癌我们证明了约40%的切除的肺肿瘤过表达NotchS。在 在肺发育中，组成型激活的NotchS阻止肺上皮的成熟。此外，委员会认为， 抑制NotchS可降低肿瘤表型，诱导凋亡，并使肿瘤细胞变得更 依赖外源性生长因子。最后，Notch激活的药理学抑制降低了 体外肺癌增殖。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起作用，并且是治疗肺癌的潜在靶点。 干预为了验证这些假设，（1）我们将检查NotchS是否足以用于细胞免疫。 使用可诱导的、Clara细胞驱动的NotchS表达小鼠模型在体内转化。(2)而 转化是癌症发病机制中的一个重要方面，了解NotchS是否 在发展中也很重要。我们将研究抑制NotchS对肿瘤的影响， 使用原位肺癌模型在已建立肿瘤中的存活、进展和转移。（三） γ-分泌酶是蛋白水解切割所必需的含早老素的蛋白复合物， Notch受体的激活。在这个目标中，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作用，并确定抗肿瘤抑制剂 效果与Notch有关。这些拟议的研究将有可能确定NotchS作为靶点， 干预，并提供NotchS相关的肺癌发病机制的见解。

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.