PPAR gamma Agonists for Lung Cancer Chemoprevention

PPAR γ 激动剂用于肺癌化学预防

• 批准号: 8922356
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922356
• 关键词: Adopted; Affect; Agonist; Alveolar; Alveolar Macrophages; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biopsy; Bronchoalveolar Lavage; Cancer Etiology; Cancer Model; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Chest; Clinical; 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; Human; Iloprost; In Vitro; Inflammatory; Laboratories; Lead; Lesion; Lung; 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; Premalignant; Production; Property; Prostaglandin Receptor; Prostaglandins; Prostaglandins I; Protein Array; Research; Risk; Role; Smoker; Smoking; Smoking Prevention; Squamous Cell; Staging; Survival Rate; Testing; Tobacco Dependence; Transcription Coactivator; Transforming Growth Factors; Treprostinil; United States; Veterans; Woman; Work; X-Ray Computed Tomography; analog; antitumor effect; cancer chemoprevention; cancer diagnosis; chemokine; curative treatments; cytokine; experience; high risk; improved; low-dose spiral CT; lung cancer screening; lung tumorigenesis; macrophage; men; mortality; mouse model; novel; patient population; preclinical study; prevent; programs; public health relevance; research study; response; screening; smoking cessation; success; tumor growth; tumor microenvironment

 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，由于军事人员获得的烟草成瘾率很高，因此退伍军人事务部仍然是退伍军人事务部的医疗优先事项。最近的数据显示，活跃军事人员的吸烟率实际上增加，而退伍军人的吸烟率始终比普通人群高10％（29％比18％）。肺癌的五年生存率仍然保持16％，在过去的几十年中，这种率有限。在退伍军人中，目前只有16％的肺癌被诊断出在可治愈的阶段。大规模筛查试验（最著名的是国家肺筛查试验-NLST），与胸部X射线相比，低剂量CT扫描被证明可显着降低肺癌死亡率（20％）。许多小组认可了肺癌的CT筛查，正在进行VA实施研究。如果在高风险组中广泛采用CT筛查（由NLST定义），则患有可治愈疾病的患者应增加（I阶段I和II阶段），从而提高总体生存率。提高的生存率将导致第二次原发性肺癌在RIS的患者人数越来越大。治疗治疗后第二次原发性肺癌的风险范围为3-6％。以前的吸烟者也处于肺癌的高风险，在该组中，在美国诊断的50％以上。在这个大型高危人群中，化学预防药物的潜在临床影响强调了继续研究的需求。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，在上一个赠款周期内完成的肺部肿瘤发生中，这些类花生素的平衡是关键的机械研究，这表明观察到的化学预防可能直接来自PGI2和PGI2类似物吸引转录激活剂PPAR（过氧化物体膨胀剂增殖受体激活的受体γ）。这些发现，再加上临床研究，观察到服用PPARS激动剂糖尿病的退伍军人中肺癌降低了33％，这表明PPAR®激动剂可能预防肺癌。我的VA资助的实验室专注于评估PGI2作为化学预防剂，并且PGI2水平升高或接受PPAPER的动物受到保护，可保护不受肺癌的发展。最重要的是，这导致了一项II期临床试验，该试验显示口腔伊洛列优先菌改善了以前吸烟者的支撑损伤。我们目前的人类试验是评估吡格列酮是高风险当前和前吸烟者。拟议的研究：这项批准提出了在方形细胞肺癌模型中促进PPARS激动剂进行临床前研究的提议，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Pioglitazone）将化学预防支撑型发育异常和肺部肿瘤的发展，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影响促肿瘤和抗生长因子的产生来促进抗肿瘤作用。假设2：选择性PPAR®激动剂（内源性前列环蛋白和吡格列酮）化学预防通过改变炎症细胞种群和巨噬细胞型，可以改变鼠类鳞状细胞肺癌和前神经支架前肿瘤的发展。