TARGETING NOTCH 3 IN LUNG CANCER

针对肺癌的第 3 级治疗

• 批准号: 7799945
• 负责人: Thao P. Dang
• 金额: $ 21.23万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7799945
• 关键词: Animals; Antibodies; Antibody Affinity; Automobile Driving; Biological Markers; Blocking Antibodies; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Trials; Data; Dependence; EGF gene; Elements; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Family; Genes; Growth Factor; Human; In Vitro; Link; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular Target; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Peptides; Phase; Phase II Clinical Trials; Principal Investigator; Process; Recombinant Antibody; Refractory; Reproduction spores; Resected; Role; Screening procedure; Serum; Signal Pathway; Signal Transduction; Specificity; System; Testing; Therapeutic; Tyrosine Kinase Inhibitor; United States; Xenograft Model; Xenograft procedure; in vivo; inhibitor/antagonist; malignant phenotype; malignant state; member; new therapeutic target; notch protein; novel therapeutics; pneumocyte; pre-clinical; programs; receptor; research clinical testing; secretase; tumor; tumor growth; tumor xenograft; tumorigenesis

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.

肺癌是美国与癌症相关死亡的最常见原因。治愈 晚期肺癌患者的速度仍然很低，在过去的30个患者中没有显着变化 年。更好地理解对驾驶和维持恶性肿瘤重要的信号通路 状态对于持续治疗肺癌患者的持续进展很重要。缺口家族 已证明受体在细胞命运测定和肿瘤发生中都很重要。 尽管Notch途径在人类癌症中的作用越来越大，但对 Notch3及其在肺癌中的效应子。我们是第一个将Notch3途径失调失调的人 人肺癌。我们证明了在所有切除的肺癌中的40％中，Notchs高度表达 在发育中的肺中，Notchs的本构激活导致抑制终端 肺细胞的分化。此外，我们已经表明，在人肺中抑制这种途径 使用异种移植模型，肿瘤在体外和体内导致恶性表型的丧失。这 在低血清的存在并与EGFR酪氨酸激酶结合使用的情况下，抗肿瘤效应得到增强 抑制剂。综上所述，我们的数据支持Notchs受体及其与之相互作用的重要作用 肺癌中的EGF和RAS途径。此外，我们现在有来自体外和IN的大量证据 体内研究，可以通过抑制所需的受体加工有效地阻断Notch信号传导 默克公司＆Co。的Y-分泌酶抑制剂，目前正在I期人类临床试验中。 在此提案中，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类临床测试。此外，我们还建议在生物学上发展 活跃的重组抗体靶向缺口。这两种方法都代表了新颖的治疗性 治疗肺癌患者的策略。