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

描述(由申请人提供)：受体酪氨酸激酶(RTK)已被证明是治疗肺癌的重要靶点。然而，即使在抑制RTK表皮生长因子受体的情况下，小分子抑制剂对难治性晚期非小细胞肺癌的反应也最多只有5%-15%。我们最近发现c-Met在非小细胞肺癌中高表达，可能成为肺癌治疗的一个重要靶点。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等过程中发挥重要作用。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、71%的鳞癌组织和78%的大细胞癌组织与邻近的正常组织相比有c-Met的过表达。在一些NSCLC肿瘤组织样本中，我们还发现c-Met被激活(位于pY1003的膜旁区域和pY1230/1234/1235的自磷酸化位点)。作为初步数据，我们已经分析了127例肺腺癌肿瘤组织中的c-Met基因，并发现了c-Met调控膜旁结构域和信号素结构域(位于c-Met末端)的独特突变。有趣的是，我们没有在c-Met的酪氨酸激酶结构域中发现任何突变。我们也已经能够获得针对c-Met的小分子抑制剂和抑制性抗体，并在NSCLC细胞系和体内小鼠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。我们将通过以下具体目的来确定c-Met在非小细胞肺癌中的具体作用和c-Met的治疗靶向性：1.确定c-Met/HGF轴和c-Met突变在非小细胞肺癌细胞生物学和生化功能中的作用；2.确定抑制c-Met在非小细胞肺癌中的体内外效应；3.确定c-Met/HGF信号转导和抑制对非小细胞肺癌PI3K/AKT/mTOR通路的影响；4.进行抗c-Met I/I期临床试验。通过实现这些特定目标中提出的目标，我们将获得针对c-Met的肺癌新疗法。

DESCRIPTION (provided by applicant): 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 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.