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）： 背景资料：肺癌是美国男性和女性癌症死亡的头号原因，由于军人吸烟成瘾率高，肺癌仍然是退伍军人事务部确定的医疗优先事项。最近的数据显示，现役军人的吸烟率实际上有所增加，退伍军人的吸烟率始终比普通人群高出至少10%（29%对18%）。肺癌的五年存活率仍然是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%的肺癌被诊断为可治愈阶段。大规模筛查试验（最值得注意的是国家肺筛查试验- NLST）已经完成，与胸部X光相比，低剂量CT扫描被证明可以显着降低肺癌死亡率（20%）。CT筛查肺癌已得到许多团体的认可，目前正在进行VA实施研究。如果CT筛查在高危人群（如NLST所定义）中广泛采用，那么出现可治愈疾病（I期和II期）的患者应该会增加，从而提高总生存率。生存率的提高将导致越来越多的第二原发性肺癌患者面临风险。根治性治疗后发生第二原发性肺癌的风险为3- 6%。前吸烟者患肺癌的风险也很高，在美国，超过50%的肺癌被诊断为这一组。化学预防剂在这一庞大的高危人群中的潜在临床影响强调了继续研究的必要性。提高降低肺癌发病率的成功率不仅依赖于预防吸烟和戒烟，还依赖于有效的化学预防策略。完成的工作：前列环素（前列腺素I2，PGI 2）是一种天然存在的类二十烷酸，具有抗炎和抗转移特性，以及抑制肿瘤生长的作用。我们已经发现，这些类花生酸的平衡在肺肿瘤发生中是关键的，并且在上一个资助周期中完成的关键机制研究表明，所观察到的化学预防可能直接来自于PGI 2和PGI 2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，再加上临床研究观察到服用PPAR <$激动剂治疗糖尿病的退伍军人肺癌发病率降低33%，表明PPAR <$激动剂可能预防肺癌。我的VA资助的实验室专注于评估PGI 2作为一种化学预防剂，PGI 2水平升高或接受PPAR？激动剂的动物不会患肺癌。最重要的是，这导致了一项II期临床试验，该试验显示口服伊洛前列素改善了前吸烟者的支气管内损伤。我们目前的人体试验是评估吡格列酮是高风险的当前和以前的吸烟者。拟定研究：该补助金旨在推进鳞状细胞肺癌模型中的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，活化剂（内源性PGI 2和吡格列酮）将化学预防支气管内发育不良和肺肿瘤的发展，并将通过影响炎性细胞募集和表型来改变TME。将检验以下假设：假设1：PPAR β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效应。假设二：选择性过氧化物酶激活受体？激动剂（内源性前列环素和吡格列酮）通过改变炎性细胞群和巨噬细胞表型来化学预防鼠鳞状细胞肺癌和癌前支气管发育不良的发展。