Role of hormone pathways in chemoprevention for high risk smokers

 简介(申请人提供)：戒烟后，戒烟者仍有罹患肺癌的风险，占新诊断肺癌的50%。烟草暴露会导致呼吸道癌前病变的发展，经过几个组织学严重阶段的进展，并在戒烟后持续存在。伊洛前列素是一种前列环素类似物，主要通过激活过氧化体增殖物激活受体γ(PPARγ)途径发挥作用，在预防肺癌方面取得了进展。在一项随机安慰剂对照试验中，与安慰剂相比，口服伊洛前列素治疗高危既往吸烟者改善了呼吸道组织学评分和异常增生指数。这一发现表明，使用伊洛前列素等PPARγ激动剂可以减轻癌症前的呼吸道负担。预测创业综合症和/或对伊洛前列素耐药的生物标志物将有助于建议与伊洛前列素联合使用以提高疗效的药物。在R21的应用中，我们将检测雌激素受体(ER)途径中蛋白质的表达与高危吸烟者异型增生的严重程度或持续性的相关性(目标1)。根据我们的初步数据，雌激素受体(ER)途径与肺癌密切相关，是鉴定呼吸道侵袭性癌前病变的候选途径。我们还将确定在动物化学预防研究中单独使用抗雌激素药物和联合激活PPARγ的有效性，以获得临床前数据，以支持在人体试验中测试这种组合(目标2)。最后，我们 将确定ER途径蛋白是否与从正在进行的化学预防临床试验中收集的生物标本中对PPARγ激动剂吡格列酮的耐药性有关，以测试ER途径蛋白作为异型增生持续和/或对PPARγ激动剂应答的生物标志物的预测价值(AIM 3)。

 DESCRIPTION (provided by applicant): Former smokers remain at risk for lung cancer after smoking cessation, and make up 50% of new lung cancer diagnoses. Tobacco exposure leads to development of preneoplastic lesions in the airways, which progress through several stages of histologic severity, and which can persist after smoking cessation. Progress in lung cancer prevention was achieved with iloprost, a prostacyclin analog that works mainly through activation of the peroxisomal proliferator-activated receptor γ (PPARγ) pathway. In a randomized placebo-controlled trial, oral iloprost treatment in high-risk former smokers improved both airway histology scores and the dysplasia index compared to placebo. This finding shows that reduction in the burden of airway premalignancy is feasible with PPARγ agonists such as iloprost. Biomarkers that predict potential for persistence of preneoplasias and/or resistance to iloprost would be useful in suggesting agents that might be combined with iloprost to improve efficacy. In this R21 application, we will examine expression of proteins in the estrogen receptor (ER) pathway for association with severity or persistence of dysplasia found in high-risk smokers (Aim 1). The estrogen receptor (ER) pathway has been strongly implicated in lung cancer and is a candidate pathway for identification of aggressive preneoplastic lesions in the airway, based on our preliminary data. We will also determine the efficacy of an anti-estrogen alone and in combination with PPARγ activation in chemoprevention studies in animals, to obtain preclinical data in support of testing this combination in human trials (Aim 2). Finally, we will determine if ER pathway proteins are associated with resistance to the PPARγ agonist pioglitazone in biospecimens collected from an on-going chemoprevention clinical trial, to test the predictive value of ER pathway proteins as biomarkers of dysplasia persistence and/or response to a PPARγ agonist (Aim 3).