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.

Public Health Relevance

Lung tumors with K-ras mutation are resistant to current therapies. This SPORE project will take advantage of an inflammatory pathway that is up-regulated by K-ras mutation, which can be targeted by a new class of drugs, the neutrophil elastase inhibitors. These drugs are being tested in human to treat chronic obstructive pulmonary disease (COPD), and this project will use human lung tumors and animal models of lung cancer to develop a rationale for the use of these drugs in patients with K-ras mutant tumors.

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National Cancer Institute (NCI)
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University of Pittsburgh
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