EGFR Mutations in non-Small Cell Lung Cancer

非小细胞肺癌中的 EGFR 突变

• 批准号: 6906935
• 负责人: BRUCE E. JOHNSON
• 金额: $ 29.68万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906935
• 关键词: cell line; clinical research; epidermal growth factor; gender difference; gene mutation; genetic susceptibility; growth factor receptors; human subject; kinase inhibitor; neoplasm /cancer genetics; neoplastic growth; nonsmall cell lung cancer; nucleic acid sequence; receptor sensitivity

DESCRIPTION (provided by applicant): Non-small cell lung carcinoma is responsible for approximately 85% of lung cancer and existing treatments for patients with advanced disease remain only marginally effective. Agents directed against the epidermal growth factor receptor have been developed (EGFR). However, only 10-20% of patients with relapsed non-small cell lung cancer have a partial or complete response to treatment with the common EGFR inhibitors, gefitinib and erlotinib. Point mutations and deletions in EGFR are associated with clinical responses to gefitinib in nearly all patients. Tumor cell lines with EGFR mutations are also sensitive to gefitinib treatment in vitro. This proposal is to further characterize the mutations in the EGFR in the tumors and tumor cell lines from subjects with non-small cell lung cancer. Aim 1 will be to establish the frequency and type of mutations in the epidermal growth factor receptor in previously untreated patients with advanced non-small cell lung cancer prospectively entered into trials using epidermal growth factor receptor inhibitors. We have two patient cohorts of 135 patients with advanced non-small cell lung cancer who are going to be studied. These cohorts will include those who respond to treatment, patients with stable disease, and patients with progressive non-small cell lung cancer. Aim 2 is to determine the relationship between epidermal growth factor receptor mutations, response to treatment, time to progression, and survival in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase. This will be done to determine if specific mutations give rise to different patient outcomes that include response, duration of response, and survival. We have assembled a consortium of investigators that have studied untreated patients with non-small cell lung cancer given single agent EGFR inhibitors to enable us to assemble multiple large groups of patients with responses and EGFR mutations. Aim 3 will be to study the tumors and tumor cell lines from patients with non-small cell lung cancer before and after treatment with EGFR inhibitors to determine the relationship between genetic changes and sensitivity and resistance to epidermal growth factor receptor inhibitors. NCI-H3255 and DFCI-LU- 011 are adenocarcinoma cell lines with EGFR mutations. Their sensitivity to EGFR inhibitors, downstream signaling events, and the mechanism of cell death compared to cell lines with wild type EGFR will be studied. These studies will provide guidance for future trials of EGFR inhibitors.

描述（由申请人提供）：非小细胞肺癌造成约85％的肺癌和晚期疾病患者的现有治疗方法仅略有效率。已经开发了针对表皮生长因子受体的药物（EGFR）。但是，只有10-20％的复发非小细胞肺癌患者对使用常见的EGFR抑制剂Gefitinib和Erlotinib的治疗有部分或完全反应。 EGFR中的点突变和缺失与几乎所有患者的吉非替尼的临床反应有关。具有EGFR突变的肿瘤细胞系在体外也对吉非替尼治疗敏感。该建议是为了进一步表征来自非小细胞肺癌受试者的肿瘤和肿瘤细胞系中EGFR的突变。 AIM 1将是在先前未经治疗的非小细胞肺癌先前未经治疗的患者中建立表皮生长因子受体的频率和类型，前瞻性地使用表皮生长因子受体抑制剂进入试验。我们有两名患者人群，其中135例晚期非小细胞肺癌患者将被研究。这些队列将包括对治疗，稳定疾病患者以及进行性非小细胞肺癌患者的反应的人。 AIM 2是确定表皮生长因子受体突变，对治疗的反应，进展的时间以及用表皮生长因子受体受体酪氨酸激酶治疗的非小细胞肺癌患者的生存。这将是为了确定特定突变是否引起不同的患者结局，包括反应，反应持续时间和生存。我们组装了一个研究人员的联盟，这些研究人员研究了未经治疗的非小细胞肺癌患者，给定单位药物EGFR抑制剂，使我们能够组装有反应和EGFR突变的多组大型患者。 AIM 3将是在用EGFR抑制剂治疗前后研究来自非小细胞肺癌患者的肿瘤和肿瘤细胞系，以确定遗传变化与敏感性与对表皮生长因子受体抑制剂的抗性之间的关系。 NCI-H3255和DFCI-LU-011是具有EGFR突变的腺癌细胞系。与野生型EGFR相比，它们对EGFR抑制剂，下游信号事件和细胞死亡机制的敏感性将得到研究。这些研究将为EGFR抑制剂的未来试验提供指导。