Targeting Neutrophil Elastase in Lung Cancer

这个新的SPORE项目将测试NE是炎症的关键介质的整体假设 在人肺癌中，特别是在K-ras突变的人肺肿瘤中， NE含量高。我们的初步数据表明NE介导的IRS-1降解促进了 肺肿瘤干扰NE功能可能抑制对其他化疗药物耐药的K-ras突变型肺癌。 靶向治疗。长期目标是抑制NE作为治疗肺癌的新疗法。到 为实现这一目标，我们提出三个具体目标：1.为了确定K-ras/NE/IRS的临床相关性， 1信号通路在非小细胞肺癌（NSCLC）中的作用， 我们肺癌孢子组织库的病例我们假设中性粒细胞和NE含量是 与患者结果呈负相关，而IRS-1与患者结果直接相关。此外，委员会认为， 我们假设K-ras突变型肺肿瘤具有最大的中性粒细胞/NE和最少的IRS-1含量。 肺气肿或患者存在气流阻塞也可能与中性粒细胞和 NE肿瘤含量和降低的IRS-1含量。2.我们将确定α-1-抗胰蛋白酶（α 1-AT， 天然NE抑制剂）以及相关肺临床前模型中的合成低分子量NE抑制剂 腺癌为了测试功效，我们将使用腺癌的Kras转基因模型和 在有或没有香烟烟雾的情况下使用NNK诱导肺肿瘤， 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 将比较媒介物处理的和NE受体处理的动物中的基因型。生物标志物相关的 NE/IRS-1通路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.到该项目的第四年，我们将开始使用NE抑制剂进行临床试验， 辅助治疗切除的NSCLC。我们假设NE抑制将改善无疾病 以顺铂为基础的辅助化疗后的生存率。提出了一项II期试验设计， 与α 1-AT或小分子量NE抑制剂一起使用。我们假设K-ras基因阳性的NSCLC 突变将受益于NE抑制剂治疗。根据NE抑制剂对K-ras的作用结果， 野生型肿瘤的临床前模型，这类药物也可以预测有价值的患者 K-ras野生型基因型，可能是肺气肿。发现受NE调节的生物标志物 还将在经历NE抑制剂治疗的患者中检查临床前模型中的NE抑制剂治疗。

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.