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

COPD 和肺癌中前列环素-PPARy 轴的共同靶向

• 批准号: 8490706
• 负责人: MARK W GERACI
• 金额: $ 56.42万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490706
• 关键词: Adrenal Cortex Hormones; Aging; Agonist; Ally; Animal Model; Anti-Cholinergics; Antioxidants; Apoptotic; Biological Markers; Breathing; Cell Aging; Cells; Chemopreventive Agent; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical Trials; Data; Development; Disease; Disease Progression; Dysplasia; Environmental Risk Factor; Etiology; Extracellular Matrix; FDA approved; Failure; Funding; Genotoxic Stress; Goals; Human; Iloprost; Image; Individual; Inflammation; Inflammatory; Intervention; Intraepithelial Neoplasia; Investigation; Lead; Ligands; Link; Lung; Lung Inflammation; Lung Neoplasms; Lung diseases; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Modeling; Modification; Molecular; Mus; Obstruction; Organ; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Pioglitazone; Positioning Attribute; Premalignant; Process; Prostaglandins I; Proteolysis; Pulmonary Emphysema; Research; Retinoids; Risk; Safety; Signal Transduction; Smoke; Smoker; Structure of parenchyma of lung; Supplementation; Testing; Tobacco; Tobacco smoke; Vitamins; analog; base; cancer chemoprevention; cancer risk; disease phenotype; high risk; insight; lung carcinogenesis; lung injury; neoplastic; novel; preclinical study; research study

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.

描述（由申请人提供）：气流阻塞，慢性支气管炎或肺气肿具有重叠的COPD表型的吸烟者具有明显更高的肺癌风险，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是肺癌风险比螺旋空气流阻塞更强大的预测因素。肺部炎症和过度的细胞外基质蛋白水解已被烟草烟雾介导为肺损伤的介体。此外，烟草烟雾触发的氧化应激会引起肺部炎症，并逐渐破坏参与肺完整性维持的细胞信号传导，最终导致器官衰老和细胞衰老。目前尚无针对肺组织破坏逆转并促进保护肺组织的分化的烟草烟雾引起的肺部疾病的特定治疗方法。我们的目标是基于保护肺组织免受两种烟草诱导疾病的发病机理的机械研究，开发出靶向COPD进展和肺癌的新型治疗方法。我们的临床前研究表明，补充前列环蛋白可以预防烟草烟雾引起的肺部疾病，包括COPD和肺癌之前观察到的肿瘤前变化。我们假设前列环蛋白-PPAR3轴具有前列环蛋白类似物和PPAR3激动剂对烟草烟雾诱导的肺部疾病具有细胞保护作用，从而导致COPD患者的肺部破坏以及对癌症的上皮性浮肿向癌症的过渡的肺部破坏。在特定的目标1中，我们将确定PPAR3信号增强是否具有分化的促分化，对患有肺癌风险的个体的化学预防作用，并减少COPD患者的肺部炎症。在特定的目标2中，我们将追求炎症生物标志物，这些炎症生物标志物是反应者而不是对PPAR3修改疗法的无反应者。在特定的目标3中，我们将在鼠模型中证明PPAR3信号增强疗法（伊洛前列素或吡格列酮）会减少烟草烟雾引起的肺损伤。从而减少烟草烟雾诱导的肺肿瘤的发生。由于所研究的药物已经通过既定的安全概念批准了FDA，因此我们的研究可能很快就会产生新的治疗方法，以靶向肺组织破坏的逆转并促进烟草烟雾诱发的肺部疾病COPD和肺癌的肺组织保护。