Common targeting of the prostacyclin-PPARy axis in COPD and lung cancer

描述（由申请人提供）：具有气流阻塞、慢性支气管炎或肺气肿重叠 COPD 表型的吸烟者患肺癌的风险显着更高，因为最近的两项研究表明，通过 CT 成像检测到的肺气肿可能比肺活量气流阻塞更能预测肺癌风险。肺部炎症和过度的细胞外基质蛋白水解被认为是烟草烟雾造成的肺损伤的介质。此外，烟草烟雾引发的氧化应激会引发肺部炎症，并逐渐破坏参与维持肺部完整性的细胞信号传导，最终导致器官衰老和细胞衰老。目前还没有针对烟草烟雾引起的肺部疾病的具体治疗方法，以逆转肺组织破坏并促进分化以保护肺组织。我们的目标是基于对保护肺组织免受烟草烟雾诱发疾病发病机制影响的分子途径的机制研究，开发同时针对慢性阻塞性肺病进展和肺癌的新型治疗方法。我们的临床前研究证明，补充前列环素可以预防烟草烟雾诱发的肺部疾病，包括慢性阻塞性肺病和肺癌之前观察到的肿瘤前变化。我们假设，用前列环素类似物和 PPAR3 激动剂激活前列环素 - PPAR3 轴，对烟草烟雾诱发的肺部疾病具有细胞保护作用，从而导致 COPD 患者同时免受肺破坏和上皮发育不良向癌症的转变。在具体目标 1 中，我们将确定 PPAR3 信号传导增强是否对有肺癌风险的个体具有促分化和化学预防作用，并减少 COPD 患者的肺部炎症。在具体目标 2 中，我们将寻找能够表征 PPAR3 修饰疗法有反应者与无反应者特征的炎症生物标志物。在具体目标 3 中，我们将在小鼠模型中证明 PPAR3 信号增强疗法（伊洛前列素或吡格列酮）可以减轻烟草烟雾引起的肺损伤；从而减少烟草烟雾诱发的肺部肿瘤的发生。由于正在研究的药物已获得 FDA 批准并具有既定的安全性，因此我们的研究可能会相对较快地产生新的治疗方法，以逆转肺组织破坏并促进肺组织保护，以治疗烟草烟雾引起的肺病 COPD 和肺癌。 公共卫生相关性：烟草烟雾会导致肺癌和慢性阻塞性肺病 (COPD)。最近的数据显示，患有严重慢性阻塞性肺病的患者患肺癌的风险增加。我们的提案旨在表明 FDA 批准的两种药物伊洛前列素和吡格列酮不仅可以防止癌前病变的进展，还可以保护患有慢性阻塞性肺病的患者。我们依靠已经正在进行并资助的临床试验来研究这两种药物的有益效果。我们的实验目标是识别生物标志物，这些生物标志物可用于识别对这两种药物有反应的个体。我们的实验还涉及动物模型中最先进的研究，以阐明这些药物如何发挥保护肺部的作用。

DESCRIPTION (provided by applicant): Smokers with the overlapping COPD phenotypes of airflow obstruction, chronic bronchitis or emphysema carry a significantly higher risk of developing lung cancer, as two recent studies indicated that emphysema detected by CT imaging may be a stronger predictor of lung cancer risk than spirometric airflow obstruction. Lung inflammation and excessive extracellular matrix proteolysis have been implicated as mediators of lung injury by tobacco smoke. Furthermore, tobacco smoke-triggered oxidative stress initiates lung inflammation and progressively disrupts cellular signaling involved in maintenance of lung integrity, eventually leading to organ aging and cell senescence. There are as yet no specific treatments for tobacco smoke-induced lung diseases that target the reversal of lung tissue destruction and promote differentiation for protecting lung tissue. Our goal is to develop novel treatments that target COPD progression and lung cancer simultaneously, based on mechanistic studies of molecular pathways that protect lung tissue from the pathogenesis of both tobacco-smoke induced diseases. Our preclinical studies have documented that prostacyclin supplementation protects against tobacco smoke-induced lung diseases, including COPD and the pre-neoplastic changes observed prior to lung cancer. We hypothesize that activation of the prostacyclin - PPAR3 axis with prostacyclin analogues and PPAR3 agonists has cytoprotective effects in tobacco smoke-induced lung disease, leading to concomitant protection from lung destruction in patients with COPD and development of the transition of epithelial dysplasia to cancer. In specific aim 1, we will determine whether PPAR3 signaling enhancement has a pro-differentiation, chemopreventive effect in individuals at risk for lung cancer and decreases lung inflammation in COPD patients. In specific aim 2, we will pursue inflammation biomarkers that characterize responders versus non-responders to PPAR3 modifying therapies. In specific aim 3, we will demonstrate in murine models that PPAR3 signaling enhancing therapies (iloprost or pioglitazone) can diminish tobacco smoke-induced lung injury; thereby decreasing the occurrence of tobacco smoke-induced lung tumors. Because the drugs being studied are already FDA approved with established safety profiles, our research could yield new treatments relatively soon that target the reversal of lung tissue destruction and promote lung tissue protection for the tobacco smoke-induced lung diseases COPD and lung cancer. PUBLIC HEALTH RELEVANCE: Tobacco smoke causes both lung cancer and chronic obstructive pulmonary disease (COPD). There is recent data showing that patients with severe COPD are at an increased risk of developing lung cancer. Our proposal seeks to show that two FDA approved drugs, iloprost and pioglitazone, can not only protect against the progression of precancerous changes but also protect the patients that have COPD. We rely on already ongoing and funded clinical trials to investigate the beneficial effects of both drugs. Our experiments target the identification of biomarkers that can be used to identify those individuals who respond to both drugs. Our experiments also involve state of the art investigations in animal models to clarify how these drugs act to protect the lung.