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

• 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
• 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

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，即使有RTK表皮生长因子受体的抑制，反应 在难治性晚期非小细胞肺癌中，使用小分子抑制剂最好为5%-15%。我们最近做了 发现c-Met在非小细胞肺癌和非小细胞肺癌中高表达，并可能作为一种 肺癌的重要治疗靶点。C-Met是一种RTK，在细胞增殖、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，我们发现69%的 腺癌组织样本、71%的鳞癌样本和78%的大细胞样本 与癌旁正常组织相比，癌组织有c-Met的过度表达。在一些 在非小细胞肺癌肿瘤组织样本中，我们还发现c-Met(在膜旁区域 PY1003和pY1230/1234/1235上的自动磷酸化位点)。作为初步数据，我们有 对127例肺腺癌组织标本进行了c-Met基因分析，并对c-Met基因进行了鉴定 调控膜旁结构域和信号素结构域(末端)的独特突变 C-Met)。有趣的是，我们没有发现c-酪氨酸激酶结构域有任何突变。 相遇了。我们还获得了小分子抑制剂和针对c-DNA的抑制性抗体。 在NSCLC细胞系和小鼠体内异种移植模型中显示出特异性的生长抑制。 我们的假设是c-Met是非小细胞肺癌重要的治疗靶点。我们将确定 C-Met在非小细胞肺癌中的特殊作用及c-Met的靶向治疗作用：1. 确定c-Met/HGF轴和c-Met突变在生物学和生化功能中的作用 抑制非小细胞肺癌细胞c-Met的体内外效应 3.确定c-Met/HGF信号通路及其抑制对PI3K/AKT/mTOR的影响 进行抗c-Met I/I期治疗非小细胞肺癌的临床试验。通过 实现这些具体目标中提出的目标，我们将达到对抗c-C-C的新疗法。 在肺癌中相遇。