TARGETING NOTCH 3 IN LUNG CANCER

肺癌是美国癌症相关死亡的最常见原因。治愈 晚期肺癌患者的死亡率仍然很低，在过去的30年里没有显著变化。 年更好地理解在驱动和维持恶性肿瘤中重要的信号通路， 对于肺癌患者治疗的持续进展来说，国家是重要的。Notch家族 已经证明，受体在细胞命运决定和肿瘤发生中都是重要的。 尽管Notch通路在人类癌症中的作用越来越大，但对Notch通路的作用知之甚少。 Notch 3及其在肺癌中的效应。我们是第一个将Notch 3通路的失调与 人类肺癌我们证明NotchS在所有切除的肺癌中有40%高度表达 并且，在发育中的肺中，NotchS的组成性激活导致终末转录因子的抑制。 肺细胞的分化。此外，我们已经表明，抑制人肺中的这一通路， 在体外和使用异种移植模型的体内，肿瘤导致恶性表型的丧失。这 在低血清存在下并与EGFr酪氨酸激酶组合时， 抑制剂.综上所述，我们的数据支持NotchS受体的重要作用及其与细胞的相互作用。 EGF和ras在肺癌中的作用此外，我们现在有强有力的证据，无论是在体外， 体内研究表明，Notch信号可以通过抑制所需的受体加工来有效阻断 用来自Merck Inc.的γ-分泌酶抑制剂& Co.，目前正在进行I期人体临床试验。 在本提案中，我们将进一步开发临床前和临床模型，以优化这些策略 使用Y-分泌酶抑制剂进行人体临床试验。此外，我们还建议进行生物开发 靶向NotchS的活性重组抗体。这两种方法都代表了新的治疗方法， 肺癌患者的治疗策略。

Lung cancer is the most common cause of cancer-related deaths in the United States. The cure rate for patients with advanced lung cancer remains low and has not changed significantly for the last 30 years. A better understanding of the signaling pathways important in driving and maintaining the malignant state is important for continued progress in the treatment of patients with lung cancer. The Notch family of receptors has been demonstrated to be important both in cell fate determination and tumorigenesis. Despite the increasing role of Notch pathway in human cancers, very little was known about the role of Notch3 and its effectors in lung cancers. We were the first to link dysregulation of the Notch3 pathway to human lung cancer. We demonstrated that NotchS is highly expressed in 40% of all resected lung cancers and that, in the developing lung, constitutive activation of NotchS results in inhibition of terminal differentiation of pneumocytes. Furthermore, we have shown that inhibiting this pathway in human lung tumors results in the loss of the malignant phenotype in vitro and in vivo using xenograft models. This antitumor effect is enhanced in the presence of low serum and in combination with an EGFr tyrosine kinase inhibitor. Taken together, our data support an important role for NotchS receptor and its interaction with the EGF and ras pathways in lung cancer. In addition, we now have strong evidence from both in vitro and in vivo studies that Notch signaling can be effectively blocked by inhibiting the required receptor processing with a y-secretase inhibitor from Merck Inc. & Co., currently in Phase I human clinical trials. In this proposal, we will further develop preclinical and clinical models to optimize these strategies using Y-secretase inhibitor for human clinical testing. Furthermore, we also propose to develop biologically active, recombinant antibody targeting NotchS. Both these approaches represent novel, therapeutic strategies in the treatment of patients with lung cancer.