Studies of a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)

非小细胞肺癌（NSCLC）新治疗靶点的研究

基本信息

批准号：
7913474
负责人：
Ravi Salgia
金额：
$ 9.8万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7913474
关键词：
Achievement Adenocarcinoma Antibodies Biochemical Biological Biology Cancer Patient Cancer cell line Carcinoma Cell Proliferation Cells Clinical Trials Data Data Analyses Disease Epidermal Growth Factor Epidermal Growth Factor Receptor Erlotinib Frequencies Gastrointestinal Stromal Tumors Gefitinib Genes Goals Growth Growth Factor Receptors Hepatocyte Growth Factor Histology In Vitro Inherited Large Cell Carcinoma Ligand Binding Ligands Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Modeling Mus Mutate Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal tissue morphology Nude Mice Papillary Pathway interactions Phase Protein Tyrosine Kinase Proto-Oncogene Protein c-kit Receptor Inhibition Receptor Protein-Tyrosine Kinases Refractory Renal Cell Carcinoma Research Personnel Role Sampling Signal Transduction Site Squamous cell carcinoma Tissue Sample Tumor Tissue Tyrosine Kinase Domain Wound Healing Xenograft Model angiogenesis cancer cell cell motility efficacy testing human FRAP1 protein improved in vivo inhibitor/antagonist lung small cell carcinoma meetings migration mouse model mutant new therapeutic target novel overexpression programs receptor response small molecule synergism therapeutic target tissue regeneration

项目摘要

Receptor tyrosine kinases (RTKs) have been shown to be important as therapeutic targets against lung cancer. However, even with the RTK epidermal growth factor receptor inhibition, the response with small molecule inhibitors is at best 5%-15% in refractory advanced NSCLC. We have recently identified that c-Met is overexpressed in NSCLC and NSCLC and may potentially serve as an important therapeutic target in lung cancer. C-Met is a RTK important in cell proliferation, motility, invasion, metastasis, angiogenesis, wound healing, and tissue regeneration. The ligand for c-Met is the hepatocyte growth factor (HGF). Utilizing immunohistochemical analysis, we show that 69% of adenocarcinoma tissue samples, 71% of squamous cell carcinoma samples, and 78% of large cell carcinomas have c-Met overexpression as compared to adjacent normal tissues. In some of the NSCLC tumor tissue samples, we also show activation of c-Met (in the juxtamembrane domain at pY1003 and autophosphorylation sites at pY1230/1234/1235). As preliminary data, we have analyzed the c-Met gene in 127 lung adenocarcinoma tumor tissue samples and have identified unique mutations in the regulatory juxtamembrane domain and the semaphorin domain (at the Nterminus of c-Met). Interestingly, we did not find any mutations in the tyrosine kinase domain of c- Met. We have also been able to obtain small molecule inhibitors and inhibitory antibodies against c- Met and show specific growth inhibition in NSCLC cell lines and in vivo mouse xenograft models. Our hypothesis is that c-Met is an important therapeutic target in NSCLC. We will determine the specific role of c-Met and therapeutic targeting of c-Met in NSCLC via these specific aims: 1. Determine the role of c-Met/HGF axis and mutations of c-Met in biological and biochemical functions of non-small cell lung cancer cells; 2. Determine the in vitro and in vivo effects of inhibiting c-Met in NSCLC; 3. Determine the effects of c-Met/HGF signaling and inhibition on PI3K/AKT/mTOR pathway in NSCLC; 4. Conduct an anti-c-Met phase I/I I clinical trial against NSCLC. Through the achievement of the goals proposed in these specific aims, we will arrive at novel therapy against c- Met in lung cancer.

受体酪氨酸激酶 (RTK) 已被证明是重要的治疗靶点肺癌。然而，即使 RTK 表皮生长因子受体抑制，反应在难治性晚期 NSCLC 中，小分子抑制剂的治疗最多为 5%-15%。我们最近有发现 c-Met 在 NSCLC 和 NSCLC 中过度表达，并可能作为肺癌的重要治疗靶点。 C-Met 是一种对细胞增殖、运动、侵袭、转移、血管生成、伤口愈合和组织再生。 c-Met 的配体是肝细胞生长因子（HGF）。利用免疫组织化学分析，我们表明 69% 腺癌组织样本、71% 的鳞状细胞癌样本和 78% 的大细胞样本与邻近的正常组织相比，癌具有c-Met过度表达。在一些 NSCLC 肿瘤组织样本中，我们还显示了 c-Met 的激活（在 pY1003 和自磷酸化位点 pY1230/1234/1235）。作为初步数据，我们有分析了 127 个肺腺癌肿瘤组织样本中的 c-Met 基因，并鉴定出调节性近膜结构域和信号蛋白结构域（位于 N 末端）的独特突变 c-Met）。有趣的是，我们没有发现 c- 的酪氨酸激酶结构域有任何突变。遇见了。我们还能够获得针对 c- 的小分子抑制剂和抑制性抗体在 NSCLC 细胞系和体内小鼠异种移植模型中满足并显示出特异性生长抑制作用。我们的假设是 c-Met 是 NSCLC 的重要治疗靶点。我们将确定 c-Met 的具体作用以及 c-Met 在 NSCLC 中的治疗靶向通过以下具体目标：1. 确定 c-Met/HGF 轴的作用以及 c-Met 突变在生物学和生化功能中的作用非小细胞肺癌细胞； 2. 确定抑制 c-Met 的体外和体内效果非小细胞肺癌； 3.确定c-Met/HGF信号传导和抑制对PI3K/AKT/mTOR的影响 NSCLC 中的通路； 4.针对NSCLC进行抗c-Met I/I I期临床试验。通过实现这些具体目标中提出的目标，我们将找到针对 c-的新疗法遇见肺癌。