PPAR gamma Agonists for Lung Cancer Chemoprevention

PPAR γ 激动剂用于肺癌化学预防

• 批准号: 8394610
• 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
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394610
• 关键词: Adenocarcinoma; Affect; Agonist; American; Americas; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biopsy; Cancer Etiology; Cancer Model; Cells; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Clinical Research; Coupled; Critical Pathways; Data; Development; Diabetes Mellitus; Diagnosis; Disabled Persons; Disease; Dysplasia; Eicosanoids; Epoprostenol; Equilibrium; Funding; Future; Gene Expression Profile; General Population; Grant; Human; Iloprost; Inflammatory; Laboratories; Lead; Lesion; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Medical; Military Personnel; Minority; Modeling; Mus; Oral; PPAR gamma; Paralysed; Pathway interactions; Patients; Phase; Phenotype; Pioglitazone; Population; Populations at Risk; Premalignant; Prevention strategy; Preventive; Property; Prostaglandins I; Research; Role; Smoke; Smoker; Smoking; Smoking Prevention; Squamous Cell; Staging; Survival Rate; Testing; Tobacco; Tobacco Dependence; Tobacco smoke; Tobacco use; Transcription Coactivator; Transgenic Mice; United States; United States Department of Veterans Affairs; Veterans; War; Woman; Work; abstracting; analog; anticancer research; cancer chemoprevention; cancer diagnosis; experience; improved; lung cancer screening; lung tumorigenesis; macrophage; men; novel; pharmacokinetic model; preclinical study; prevent; public health relevance; research study; screening; smoking cessation; success; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Merit Review Abstract: Background: Lung cancer is a major medical problem and the number one cause of cancer death in men and women in the US and worldwide. Lung cancer is a medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel and recent data shows tobacco use rates higher than that of the general public. Leading Veterans organizations (AMVETS, Disabled American Veterans, Paralyzed Veterans of America, and Veterans of Foreign Wars) have supported increased funding for early lung cancer research at the Veterans Administration. While large-scale screening trials are in progress, there are no established screening tests, and a distinct minority of patients (<25%) present with surgically curable disease (stages I and II). The cumulative five-year survival rate for lung cancer is 15%, a rate which has shown limited improvement over the last several decades. The majority of lung cancers are now diagnosed in former smokers, emphasizing the need for effective chemoprevention in this large, at-risk population. Improved success in decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on effective chemo-preventive 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. My VA funded laboratory has focused on evaluating PGI2 as a chemo-preventive agent, and transgenic mice with selective pulmonary PGIS over-expression are chemoprotected in several distinct murine adenocarcinoma models (including both chemical and tobacco-smoke exposure). We have extended our studies to animals receiving Iloprost (an oral PGI2 analogue) and have shown similar chemoprevention. Most importantly, a recent phase II clinical tria showed oral iloprost improved endobronchial damage in former smokers. Key mechanistic studies completed during the last grant cycle have shown that the observed chemoprevention may directly result from PGI2 and iloprost activating the transcription activator PPARg (peroxisome proliferator activated receptor gamma). These findings, coupled with recent clinical studies observing a 33% reduction in lung cancer rates among Veterans taking PPARg agonists for diabetes mellitus, suggest PPARg agonists may prevent lung cancer. Proposed Research: This grant proposes to advance pre-clinical studies of PPARg agonists in a squamous cell lung cancer model and a tobacco smoke exposure model. We hypothesize that PPARg activators (iloprost and pioglitazone) will chemoprevent the development of endobronchial dysplasia and lung tumors, and will alter the tumor microenvironment by affecting inflammatory cell recruitment and phenotype. The following hypotheses will be tested: Hypothesis 1: PPARg agonists (iloprost and pioglitazone) will chemoprevent the development of squamous cell lung cancer and pre-malignant endobronchial dysplasia in a murine model of squamous cell lung cancer. Hypothesis 2: PPARg agonists will chemoprevent lung cancer and premalignant lesions in a tobacco smoke model and alter inflammatory cell recruitment and activation.

描述（由申请人提供）： 功绩评论摘要：背景：肺癌是一个主要的医学问题，是美国和全球男性和女性癌症死亡的第一名。由于军事人员获得的烟草成瘾率很高，因此肺癌是退伍军人事务部的医学优先事项，最近的数据显示，烟草使用率高于公众。领先的退伍军人组织（AMVET，美国退伍军人，瘫痪的美国退伍军人和外国战争的退伍军人）支持退伍军人管理局早期肺癌研究的资金增加。尽管正在进行大规模的筛查试验，但尚无既定的筛查测试，并且有少数患者（<25％）出现了手术治愈的疾病（I和II阶段）。肺癌的累积五年存活率为15％，在过去的几十年中，这种率有限。现在，大多数肺癌在以前的吸烟者中被诊断出来，强调在这个大型高危人群中需要有效的化学预防。改善降低肺癌率的成功不仅将依赖于预防吸烟和停止，还取决于有效的化学预防策略。完成的工作：前列环素（前列腺素I2，PGI2）是一种天然存在的类花生酸，具有抗炎和抗转移性特性，并且在肿瘤生长中起着抑制作用。我们发现，这些类花生素的平衡在肺肿瘤发生中是关键的。我的VA资助的实验室专注于评估PGI2作为一种化学预防剂，而具有选择性肺PGIS过表达的转基因小鼠在几种不同的鼠类腺癌模型中进行了化学保护（包括化学和烟草 - 烟草 - 烟雾可能性暴露）。我们已经将研究扩展到接受伊洛前列素（口服PGI2类似物）的动物，并显示出相似的化学预防。最重要的是，最近的II期临床三亚临床表明，口服伊洛列优先剂改善了以前吸烟者的支撑损伤。在上一个赠款周期完成的关键机理研究表明，观察到的化学预防可能直接是由PGI2和依依前吐剂激活转录激活剂PPARG（过氧化物酶体增殖物激活的受体伽马）。这些发现，加上最近的临床研究，观察到服用PPARG激动剂糖尿病的退伍军人中肺癌降低了33％，这表明PPARG激动剂可以预防肺癌。拟议的研究：该赠款建议在鳞状细胞肺癌模型和烟草烟雾暴露模型中推进PPARG激动剂的临床前研究。我们假设PPARG活化剂（伊洛前列酮和吡格列酮）将化学预防支撑型发育不良和肺部肿瘤，并通过影响炎症细胞募集和表型来改变肿瘤微环境。将测试以下假设：假设1：PPARG激动剂（伊洛前列素和吡格列酮）将在鳞状细胞肺癌的鼠模型中化学化鳞状细胞肺癌的发展和结构性细胞肺癌的开发。假设2：PPARG激动剂将在烟草烟模型中进行化学预发的肺癌和预性病变，并改变炎症细胞的募集和激活。