Targeting Notch3 in Lung Cancer

在多细胞生物体的正常发育中至关重要的基因通常在 当在成人组织中异常表达时，肿瘤发生。Notch信号通路在细胞周期中起着至关重要的作用 细胞命运决定，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，但很少有 已知NotchS在肺癌中的作用。我们的团队是第一个将Notch3途径与 肺癌。我们证明了大约40%的切除的肺肿瘤过度表达NotchS。在 发育中的肺，结构性激活的NotchS阻止了肺上皮的成熟。此外， 抑制NotchS减少肿瘤表型，诱导细胞凋亡，使肿瘤细胞 依赖于外源生长因子。最后，药物对Notch激活的抑制减少了 肺癌体外增殖的实验研究。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作用，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 体内转化使用可诱导的Clara细胞驱动的NotchS表达小鼠模型。(2) 转化是癌症发病机制中的一个重要方面，了解NotchS是否 进步中的重要也很重要。我们将研究抑制NotchS对肿瘤的影响 基于原位肺癌模型的已建立肿瘤的存活率、进展和转移。(3) γ-分泌酶是一种含有早老素的蛋白质复合体，对蛋白水解性切割和 Notch受体的激活。在这个目标中，我们建议检测表型和生化。 γ-分泌酶抑制剂对肿瘤移植瘤的影响及抗肿瘤作用的研究 效果与凹槽相关。这些拟议的研究可能会将NotchS确定为 干预并为NotchS相关肺癌的发病机制提供洞察力。

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.