Prostanoids, Plasminogen Actication, and Personalized Therapeutics in IPF

描述（由申请人提供）：特发性肺纤维化（IPF）是一种缺乏有效治疗的肺部瘢痕性疾病，通常在几年内进展为呼吸衰竭和死亡。因此，迫切需要改善这一毁灭性疾病的治疗结果，而实现这一目标的最大障碍是缺乏在未来5-10年内切实实施的适当治疗方法。理想情况下，我们希望在我们的治疗设备中有选择的治疗方法：1)具有广泛的抗纤维化作用；2)具有可接受的安全概况；3)目前可用或预计很快可用；4)可单独使用或与其他组合使用；5)基于反应性的体外预测因子，可以以个性化的方式应用于个体患者。该提案利用了申请人团队15年的研究成果，该研究成果对目前两种符合上述潜在治疗标准的抗纤维化物质的知识做出了重大贡献：即前列腺素如前列腺素Ez （PGE2）和增强纤溶酶原激活系统的尿激酶等药物。尽管PGE2实际上抑制了正常肺成纤维细胞可能导致纤维化肺病的所有功能，但我们发现，从大多数IPF患者分离的成纤维细胞系对这种类前列腺素的通常抑制作用具有抗性。然而，我们已经确定了两种不同的分子机制来解释这种耐药性，其中一种可以通过DNA甲基化抑制剂的预处理来克服，另一种可以通过尿激酶的预处理来克服。因此，我们提出，PGE2、尿激酶、甲基化抑制剂或其组合下调患者来源的肺成纤维细胞的体外能力可以预测对这些相同方案的临床反应。基于前列腺素、尿激酶和甲基化抑制剂目前都被批准用于治疗人类疾病的事实，迫在眉睫的可行性前景。在这些研究中，我们将使用从参加Grand Opportunity COMET研究的50例具有明确特征的IPF患者的肺活检标本和支气管肺泡灌洗中分离的成纤维细胞。一组潜在的治疗药物，单独或联合，将用于治疗这两种细胞类型，以确定治疗对细胞胶原合成和增殖的影响。将比较每种细胞类型的反应模式，并将与疾病的临床进展相关联。此外，将评估这些相同方案改善博莱霉素诱导的小鼠肺纤维化的能力。这些互补方法将确定改善或阻止IPF纤维化进展的最易处理的选择，并将为未来临床试验中为患者量身定制治疗方案提供框架。因此，CADET I的成果将是一个治疗方案，可以考虑在随后的CADET II申请中提出的试验中实施。相关性（见说明书）：特发性肺纤维化（IPF）是一种致死性肺瘢痕性疾病，目前尚无有效治疗方法。前列腺素和尿激酶可对抗肺瘢痕形成。该提案将在动物模型和IPF患者的细胞中测试这些物质单独或联合改善肺瘢痕形成的能力。这些研究将确定利用这些物质的抗纤维化潜力的最佳方法，用于未来IPF患者的临床试验。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a scarring disease of the lungs for which effective therapy is lacking and which usually progresses to respiratory failure and death within several years. The need to improve outcomes in this devastating disease is therefore urgent, and the single biggest barrier to accomplishing this is the lack of appropriate treatments that can realistically be implemented within the next 5-10 years. Ideally, we would like to have in our therapeutic armamentarium a selection of treatments that: 1) have broad anti-fibrotic actions; 2) have an acceptable safety profile; 3) are currently available or expected to be available soon; 4) could be used alone or in combination with others; and 5) could be applied in a personalized fashion to individual patients, based on in vitro predictors of responsiveness. This proposal capitalizes on 15 years of research by the applicant team which has contributed substantially to current knowledge about two anti-fibrotic substances that meet the above criteria for potential therapies: namely, prostanoids such as prostaglandin Ez (PGE2) and agents such as urokinase that augment the plasminogen activation system. Although PGE2 inhibits virtually all of the functions by which normal lung fibroblasts might contribute to fibrotic lung disease, we have found that fibroblast lines isolated from the majority of individuals with IPF are resistant to the usual suppressive actions of this prostanoid. However, we have identified two distinct molecular mechanisms accounting for such resistance, one of which can be overcome by pretreatment with inhibitors of DNA methylation and the other by pretreatment with urokinase. We thus propose that the in vitro capacity of patient-derived lung fibroblasts to be down-regulated by PGE2, urokinase, methylation inhibitors, or combinations thereof could predict clinical responses to these same regimens. The prospect of imminent feasibility is based on the fact that prostanoids, urokinase, and methylation inhibitors are all currently approved for the treatment of human disease. For these studies we will employ fibroblasts isolated from lung biopsy specimens and from bronchoalveolar lavage of 50 patients with well-characterized IPF participating in our Grand Opportunity COMET study. A panel of potential therapeutic agents, alone and in combination, will be used to treat both cell types in order to determine treatment effects on cellular collagen synthesis and proliferation. Response patterns will be compared for each cell type and will be correlated with clinical progression of disease. In addition, the ability of these same regimens to ameliorate bleomycin-induced pulmonary fibrosis in mice will be assessed. These complementary approaches will determine the most tractable options for ameliorating or halting progression of fibrosis in IPF and will provide a framework for individually tailoring treatment regimens for patients in future clinical trials. The deliverable from CADET I will therefore be a menu of therapies that can be considered for implementation in trials to be proposed in a subsequent CADET II application. RELEVANCE (See instructions): Idiopathic pulmonary fibrosis (IPF) is a lethal scarring disease of the lung for which no effective therapies are currently available. Prostanoids and urokinase oppose lung scarring. This proposal will test the ability of these substances, alone and in combination, to ameliorate scar formation in the lung in both animal models and in cells from patients with IPF. These studies will identify the optimal means of harnessing the anti-fibrotic potential of these substances for future clinical trials in patients with IPF.