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PPAR gamma Agonists for Lung Cancer Chemoprevention

PPAR γ 激动剂用于肺癌化学预防

基本信息

批准号：
10058201
负责人：
Robert Keith
金额：
--
依托单位：
VA EASTERN COLORADO HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2020-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058201
关键词：
Adopted Affect Agonist Alveolar Alveolar Macrophages Animals Anti-Inflammatory Agents Biopsy Bronchoalveolar Lavage Cancer Etiology Cancer Model Cells Cessation of life Chemoprevention Chemopreventive Agent Clinical Clinical Chemoprevention Clinical Research Clinical Trials Complement Coupled Critical Pathways Data Development Diabetes Mellitus Diagnosis Dinoprostone Disease Dysplasia Eicosanoids Epoprostenol Equilibrium Exposure to Funding Future Gene Expression Profile General Population Genes Grant Growth Factor Human Iloprost In Vitro Inflammatory Laboratories Lesion Lung Lung CAT Scan Lung Neoplasms Malignant neoplasm of lung Measures Medical Military Personnel Mus Oral PPAR gamma Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phagocytosis Phase II Clinical Trials Phenotype Pioglitazone Population Populations at Risk Production Property Prostaglandin Receptor Prostaglandins Prostaglandins I Protein Array Research Project Grants Risk Role Smoker Smoking Smoking Prevention Squamous Cell Lung Carcinoma Survival Rate Testing Thoracic Radiography Tobacco Dependence Transcription Coactivator Transforming Growth Factors Treprostinil Tumor-associated macrophages United States Veterans Woman Work X-Ray Computed Tomography analog antitumor effect cancer chemoprevention cancer diagnosis carcinogenicity chemokine computed tomography screening curative treatments cytokine experience experimental study high risk high risk population improved low dose computed tomography lung cancer screening lung tumorigenesis macrophage men mortality mouse model novel patient population preclinical study premalignant prevent public health relevance recruit response screening smoking cessation success tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Background: Lung cancer is the number one cause of cancer death in men and women in the United States and remains an identified medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel. Recent data shows an actual increase in smoking rates among active military personnel and smoking rates among Veterans are consistently at least 10% higher than the general population (29% vs. 18%). The five-year survival rate for lung cancer remains 16%, a rate which has shown limited improvement over the last several decades. Among Veterans, only 16% of lung cancer is currently diagnosed at a curable stage. Large-scale screening trials (most notably the National Lung Screening trial - NLST) have been completed, and low dose CT scans were proven to significantly decrease lung cancer mortality (20%) when compared to chest x-ray. CT screening for lung cancer has been endorsed by many groups and a VA implementation study is being conducted. If CT screening is widely adopted in high risk groups (as defined by the NLST), there should be an increase in patients presenting with curable disease (stages I and II), leading to improved overall survival. Improved survival will result in a growing population of patients at ris for second primary lung cancers. The risk of developing a second primary lung cancer after curative treatment ranges from 3-6%. Former smokers are also at high risk of lung cancer, with greater than 50% of lung cancers in the US diagnosed in this group. The potential clinical impact of chemopreventive agents in this large, high-risk population emphasizes the need for continued studies. Improved success in decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on effective chemopreventive strategies. Work Accomplished: Prostacyclin (prostaglandin I2, PGI2) is a naturally occurring eicosanoid that possesses anti-inflammatory and anti-metastatic properties, as well as a suppressive role in tumor growth. We have found that the balance of these eicosanoids is pivotal in lung tumorigenesis and key mechanistic studies completed during the last grant cycle have shown that the observed chemoprevention may directly result from PGI2 and PGI2 analogues engaging the transcription activator PPAR¿ (peroxisome proliferator activated receptor gamma). These findings, coupled with clinical studies observing a 33% reduction in lung cancer rates among Veterans taking PPAR¿ agonists for diabetes mellitus, suggest PPAR¿ agonists may prevent lung cancer. My VA funded laboratory has focused on evaluating PGI2 as a chemopreventive agent, and animals with increased levels of PGI2 or receiving PPAR¿ agonists are protected from developing lung cancer. Most importantly, this led to a phase II clinical trial which showed oral iloprost improved endobronchial damage in former smokers. Our current human trial is evaluating pioglitazone is high risk current and former smokers. Proposed Research: This grant proposes to advance pre-clinical studies of PPAR¿ agonists in a squamous cell lung cancer model with a focus on the effects of PPAR¿ agonists on the tumor microenvironment (TME) and macrophage programming. We hypothesize that PPAR¿ activators (endogenous PGI2 and pioglitazone) will chemoprevent the development of endobronchial dysplasia and lung tumors, and will alter the TME by affecting inflammatory cell recruitment and phenotype. The following hypotheses will be tested: Hypothesis 1: PPAR¿ agonists promote anti-tumor effects by influencing the production of pro- and anti- growth factors by tumor associated macrophages. Hypothesis 2: Selective PPAR¿ agonists (endogenous prostacyclin and pioglitazone) chemoprevent the development of murine squamous cell lung cancer and pre-malignant endobronchial dysplasia by altering inflammatory cell populations and macrophage phenotype.

描述（由申请人提供）：背景：肺癌是美国男性和女性癌症死亡的第一大原因，并且由于军人烟瘾高发，肺癌仍然是退伍军人事务部确定的医疗重点。最近的数据显示，现役军人的吸烟率实际有所增加，而退伍军人的吸烟率始终比一般人群高出至少 10%（29% 对 18%）。肺癌的五年生存率仍然是 16%，在过去几十年中这一比率的改善有限。在退伍军人中，目前只有 16% 的肺癌被诊断出处于可治愈阶段。大规模筛查试验（最著名的是国家肺部筛查试验 - NLST）已经完成，并且与胸部 X 光检查相比，低剂量 CT 扫描被证明可显着降低肺癌死亡率 (20%)。肺癌 CT 筛查已得到许多团体的认可，并且 VA 实施研究正在进行中。如果在高危人群（如 NLST 定义）中广泛采用 CT 筛查，那么患有可治愈疾病（I 期和 II 期）的患者数量应该会增加，从而提高总体生存率。生存率的提高将导致面临第二原发性肺癌风险的患者人数不断增加。治愈性治疗后发生第二原发性肺癌的风险为 3-6%。戒烟者也是肺癌的高危人群，美国超过 50% 的肺癌患者都是由该人群诊断出来的。化学预防药物对这一庞大的高危人群的潜在临床影响强调了继续研究的必要性。降低肺癌发病率的成功不仅取决于吸烟的预防和戒烟，还取决于有效的化学预防策略。已完成的工作：前列环素（前列腺素 I2，PGI2）是一种天然存在的类二十烷酸，具有抗炎和抗转移特性，并具有抑制肿瘤生长的作用。我们发现这些类二十烷酸的平衡对于肺部肿瘤的发生至关重要，并且在上一个资助周期完成的关键机制研究表明，观察到的化学预防可能直接来自 PGI2 和 PGI2 类似物与转录激活剂 PPAR¿（过氧化物酶体增殖物激活受体 γ）的结合。这些发现，加上临床研究观察到服用 PPAR? 激动剂治疗糖尿病的退伍军人肺癌发病率降低了 33%，表明 PPAR? 激动剂可以预防肺癌。我的 VA 资助实验室专注于评估 PGI2 作为化学预防剂的作用，PGI2 水平升高或接受 PPAR¿ 激动剂的动物可以免受肺癌的侵害。最重要的是，这导致了一项 II 期临床试验，该试验表明口服伊洛前列素可改善前吸烟者的支气管内损伤。我们目前的人体试验正在评估吡格列酮是否是当前和曾经吸烟者的高风险人群。拟议研究：该资助计划在鳞状细胞肺癌模型中推进 PPAR¿ 激动剂的临床前研究，重点是 PPAR 激动剂对肿瘤微环境 (TME) 和巨噬细胞编程的影响。我们假设 PPAR 激活剂（内源性 PGI2 和吡格列酮）将化学预防支气管内发育不良和肺部肿瘤的发展，并通过影响炎症细胞募集和表型来改变 TME。将检验以下假设：假设 1：PPAR¿ 激动剂通过影响肿瘤相关巨噬细胞产生促生长因子和抗生长因子来促进抗肿瘤作用。假设 2：选择性 PPAR 激动剂（内源性前列环素和吡格列酮）通过改变炎症细胞群和巨噬细胞表型来化学预防小鼠鳞状细胞肺癌和癌前支气管内发育不良的发展。