TARGETING NOTCH 3 IN LUNG CANCER

肺癌是美国最常见的癌症相关死亡原因。解药 晚期肺癌患者的发病率仍然很低，在过去30年中没有明显变化 好几年了。更好地理解在驱动和维持恶性肿瘤过程中重要的信号通路 对于肺癌患者的治疗继续取得进展，状态是重要的。诺奇家族 受体已被证明在决定细胞命运和肿瘤发生中都起着重要作用。 尽管Notch通路在人类癌症中的作用越来越大，但人们对它的作用知之甚少。 NOTCH3及其效应因子在肺癌中的作用我们第一个将Notch3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%高表达 在发育中的肺中，NotchS的结构性激活导致末端的抑制 肺泡细胞的分化。此外，我们已经证明，在人类肺中抑制这一途径 使用异种移植模型，肿瘤在体外和体内都会导致恶性表型的丧失。这 低浓度血清与EGFR酪氨酸激酶联合应用可增强抗肿瘤作用 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 肺癌中的EGF和ras信号通路。此外，我们现在有来自体外和体内的强有力的证据。 体内研究表明，通过抑制所需的受体处理，可以有效地阻断Notch信号 使用默克公司的一种y-分泌酶抑制剂，目前正在进行第一阶段的人体临床试验。 在这个提案中，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，我们还提出了在生物上发展 针对NotchS的活性重组抗体。这两种方法都代表了新的、治疗的方法。 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.