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

受体酪氨酸激酶（RTK）已被证明是重要的治疗靶点， 肺癌然而，即使用RTK表皮生长因子受体抑制剂， 小分子抑制剂治疗难治性晚期NSCLC的最佳疗效为5%-15%。我们最近 发现c-Met在非小细胞肺癌和非小细胞肺癌中过表达，并可能作为一种潜在的治疗方法。 是肺癌重要治疗靶点。C-Met是在细胞增殖、运动性 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%的鳞状细胞癌样本，78%的大细胞癌样本， 与邻近的正常组织相比，癌具有c-Met过表达。在一些 在NSCLC肿瘤组织样本中，我们还显示c-Met的激活（在细胞膜结构域， pY 1003和pY 1230/1234/1235处的自磷酸化位点）。作为初步数据， 分析了127例肺腺癌肿瘤组织样本中的c-Met基因， 在调节质膜结构域和脑信号蛋白结构域（在N末端）中的独特突变 的c-Met）。有趣的是，我们没有发现任何突变的酪氨酸激酶结构域的c- Met.我们也已经能够获得小分子抑制剂和抑制性抗体对c- 在NSCLC细胞系和体内小鼠异种移植模型中显示特异性生长抑制。 我们的假设是c-Met是NSCLC的重要治疗靶点。康贝特人将以 c-Met的特定作用和c-Met通过这些特定目的在NSCLC中的治疗靶向：1. 确定c-Met/HGF轴的作用以及c-Met的突变在生物学和生化功能中的作用 非小细胞肺癌细胞; 2.测定在体外和体内抑制c-Met的作用， NSCLC; 3.确定c-Met/HGF信号传导和抑制对PI 3 K/AKT/mTOR的影响 NSCLC中的通路; 4.开展针对NSCLC的抗c-Met I/II期临床试验。通过 实现这些具体目标中提出的目标，我们将获得针对c- 在肺癌中相遇。

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.