Targeting Neutrophil Elastase in Lung Cancer

这个新的孢子项目将检验NE是炎症的关键介质的总体假设 人肺癌中的相关致癌信号，特别是在K-ras基因突变的人肺癌中 NE含量高。我们的初步数据显示，NE介导的IRS-1的降解促进了细胞的生长 肺部肿瘤。NE功能的中断可能会抑制K-ras基因突变的肺癌 有针对性的治疗。长期目标是抑制去甲肾上腺素作为一种治疗肺癌的新疗法。至 为了实现这一目标，我们提出了三个具体目标：1.建立K-ras/NE/IRS的临床相关性。 非小细胞肺癌(NSCLC)中的1个信号通路 从我们的肺癌孢子组织库中提取的病例。我们假设中性粒细胞和去甲肾上腺素的含量 IRS-1与患者预后呈负相关，而IRS-1与患者预后直接相关。此外， 我们推测K-ras突变肺肿瘤的中性粒细胞/NE最高，而IRS-1含量最低。 患者的肺气肿或气流阻塞也可能与中性粒细胞和 NE肿瘤含量降低，IRS-1含量降低。2.我们将确定α-1-抗胰蛋白酶(A1-AT， 天然去甲肾上腺素抑制剂)和合成低分子量去甲肾上腺素抑制剂在相关的肺临床前模型中的应用 腺癌。为了测试疗效，我们将使用Kras转基因腺癌模型和一个模型 应用NNK加和不加香烟烟雾诱导K-ras突变型肺癌 和K-ras野生型肿瘤。K-ras突变型和K-ras野生型诱导肿瘤的比例 将比较赋形剂治疗和去甲肾上腺素抑制剂治疗的动物的基因型。与之相关的生物标记物 NE/IRS-1途径以及炎症生物标志物和肺气肿的存在也将在 临床前模型。3.到这个项目的第四年，我们将启动临床试验，使用NE抑制剂治疗 手术切除的非小细胞肺癌的辅助治疗我们假设抑制去甲肾上腺素将提高无病 以顺铂为基础的辅助化疗后的存活率。一项第二阶段的试验设计被提出，它可以 可与A1-AT或小分子量去甲肾上腺素抑制剂一起使用。我们假设K-ras的非小细胞肺癌 突变将受益于去甲肾上腺素抑制剂的治疗。依赖去甲肾上腺素抑制剂对K-ras的影响 野生型肿瘤在临床前模型中，这类药物也可能预测有价值的患者 K-ras野生型，可能是肺气肿患者。发现受去甲肾上腺素调节的生物标志物 临床前模型中的抑制剂治疗也将在接受NE抑制剂治疗的患者中进行检查。

This new SPORE project will test the overall hypothesis that NE is a critical mediator of inflammation associated pro-cancer signaling in human lung cancer, especially in K-ras mutant human lung tumors with high NE content. Our preliminary data show that NE-mediated degradation of IRS-1 enhances growth of lung tumors. Interruption of NE function may inhibit K-ras mutant lung cancers that are resistant to other targeted therapies. The long-term goal is to inhibit NE as a novel therapy for treating lung cancer. To achieve this goal we propose three Specific Aims: 1. To establish the clinical relevance of the K-ras/NE/IRS- 1 signaling pathway in non-small cell lung cancer (NSCLC) by interrogating tumor tissue from well-annotated cases from our lung cancer SPORE tissue bank. We hypothesize that neutrophil and NE content are inversely correlated with patient outcome, while IRS-1 is directly correlated with patient outcome. Moreover, we hypothesize that K-ras mutant lung tumors have the greatest neutrophil/NE and the least IRS-1 content. Emphysema or presence of airflow obstruction in patients may also associate with elevated neutrophil and NE tumor content and reduced IRS-1 content. 2. We will establish the efficacy of alpha-1-antitrypsin (a1-AT, a natural NE inhibitor) as well as synthetic low MW NE inhibitors in relevant preclinical models of lung adenocarcinoma. To test efficacy, we will use the Kras transgenic model of adenocarcinoma and a model employing NNK with and without cigarette smoke to induce lung tumors that are a mixture of K-ras mutant and K-ras wild type tumors. Proportion of induced tumors that are K-ras mutant and K-ras wild-type genotype in vehicle-treated and NE inhibitor-treated animals will be compared. Biomarkers relevant to the NE/IRS-1 pathway as well as inflammatory biomarkers and presence of emphysema will also be evaluated in preclinical models. 3. By the fourth year of this project, we will initiate clinical trials using an NE inhibitor for adjuvant treatment of surgically-resected NSCLC. We hypothesize that NE inhibition will improve disease free survival followed adjuvant cisplatin-based chemotherapy. A phase II trial design is proposed that could be used with a1-AT or a small molecular weight NE inhibitor. We hypothesize that NSCLC with K-ras mutations will benefit from treatment with an NE Inhibitor. Depending on the results of NE inhibitors on K-ras wild type tumors in pre-clinical models, this class of drugs may also be predicted to have value in patients with K-ras wild-type genotype, possibly those with emphysema. Biomarkers found to be modulated by NE inhibitor treatment in preclinical models will also be examined in patients undergoing NE inhibitor treatment.