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)：具有气流阻塞、慢性支气管炎或肺气肿等COPD表型重叠的吸烟者患肺癌的风险显著更高，因为最近的两项研究表明，CT成像检测到的肺气肿可能比肺活量气流阻塞对肺癌风险的预测更强。肺部炎症和过度的细胞外基质蛋白分解被认为是烟草烟雾所致肺损伤的介质。此外，烟草烟雾引发的氧化应激引发肺部炎症，并逐渐扰乱参与维持肺完整性的细胞信号，最终导致器官老化和细胞衰老。到目前为止，还没有针对烟草烟雾引起的肺部疾病的特定治疗方法，这些疾病的目标是逆转肺组织的破坏，促进分化以保护肺组织。我们的目标是开发同时针对COPD进展和肺癌的新型治疗方法，基于对保护肺组织免受烟草引起的两种疾病发病机制的分子途径的研究。我们的临床前研究证明，补充前列环素可以预防烟草烟雾引起的肺部疾病，包括COPD和肺癌前观察到的肿瘤前变化。我们假设，前列环素-PPAR3轴被前列环素类似物和PPAR3激动剂激活在烟草烟雾诱导的肺部疾病中具有细胞保护作用，导致COPD患者的肺损伤和上皮异常增生向癌症的转变。在具体目标1中，我们将确定PPAR3信号增强是否对肺癌高危个体具有促进分化、化学预防作用，并减少COPD患者的肺部炎症。在具体目标2中，我们将寻求炎症生物标记物，以表征PPAR3修饰疗法的应答者和无应答者。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)可以减少烟草烟雾诱导的肺损伤，从而减少烟草烟雾诱导的肺肿瘤的发生。由于正在研究的药物已经获得FDA批准，并具有既定的安全性，我们的研究可能会相对较快地产生新的治疗方法，旨在逆转肺组织破坏，并促进对烟草烟雾引起的肺部疾病COPD和肺癌的肺组织保护。