Multimodal quantitative PET/MR imaging of pulmonary fibrosis

项目摘要/摘要 特发性肺纤维化(IPF)是一种破坏性的进展性疾病，中位生存期为2-4年 诊断后。三十年的研究和20多项临床试验只批准了两项 特发性肺功能衰竭的治疗：吡非尼酮和九替达尼。虽然这两种药物都能延缓疾病的发展，但也有 IPF患者个体治疗反应的差异，两种药物都不能治愈，提示IPF 可能来自不同的病理途径，导致疾病的异质性。IPF的药物开发是 受阻于糟糕的患者表型和缺乏评估疾病活动和早期治疗的工具 回应。因此，临床试验需要大量受试者观察真实的疗效信号。 多模式分子成像提供了加速药物开发并最终改变IPF管理的机会。 特定靶点的分子成像可以对受试者进行分层，评估药物与靶点的结合情况，并指导剂量 一种设计用于结合该靶点的新药的优化。分子成像也可以评估疾病的活动性。 并监测对治疗的反应。因此，一个全面的多模式分子成像协议将会改进 在较短时间内患者数量较少的情况下临床试验成功的可能性。 我们建议在小鼠肺纤维化模型中使用αvβ3整合素和氧化胶原的多模式成像。 目的：评价α-v-β-3拮抗剂作为通路特异性干预的途径。αvβ3被牵连为一种监管机构 在临床前模型和IPF患者的肺组织中，随着αvβ3表达的增加，IPF的发生发展。 在临床前模型中，αvβ3拮抗剂治疗可减少肺纤维化并提高存活率 治疗肺纤维化的药物和几种拮抗剂正在进入IPF的临床试验。正电子发射 在癌症的临床前研究中，使用18F-fpp-rGD2探针对αvβ3进行了成像。评估 疾病活动性，我们已经开发了大蒜素结合磁共振(MR)探针Gd-chyd，它报告了 在纤维化形成过程中形成的氧化胶原蛋白。我们表明，成像氧化的胶原蛋白可以预测 疾病活动性和治疗反应。由于氧化的胶原蛋白是纤维化形成的基础，Gd-chyd 可以量化肺部疾病的活动性，而不受病因的影响，通常可以用来测量反应 去接受治疗。我们将开发和优化多模式18F-FPP-RGD2 PET和Gd-Chyd磁共振成像 在小鼠肺纤维化模型中，然后用这一方法无创性地量化αvβ3的表达和 通过体外测量验证疾病进展过程中的纤维化形成。到时候我们会的 应用该方案来确认αvβ3拮抗剂的靶结合，确定最佳治疗剂量， 并用Gd-chyd磁共振进行疗效评价。我们假设分子成像将允许预先 同时评估疾病活动性和对目标的反应时目标相关性的临床评估 抑制，所有这些都将加速IPF的成功药物开发。

Project Summary/Abstract Idiopathic Pulmonary Fibrosis (IPF) is a devastatingly progressive disease with median survival of 2-4 years post diagnosis. Three decades of research and over 20 clinical trials have resulted in only two approved treatments for IPF: pirfenidone and nintedanib. While both drugs slow disease progression, there are differences in treatment response for individual IPF patients and neither drug is curative suggesting that IPF may arise from different pathologic pathways resulting in disease heterogeneity. Drug development in IPF is hampered by poor patient phenotyping and a lack of tools to assess disease activity and early treatment response. As a result, clinical trials require large numbers of subjects to observe real efficacy signals. Multimodal molecular imaging offers to accelerate drug development and ultimately change IPF management. Molecular imaging of specific targets can stratify subjects, assess drug-target engagement and guide dose optimization for a new drug designed to bind to that target. Molecular imaging also can assess disease activity and monitor response to therapy. A comprehensive multimodal molecular imaging protocol would thus improve the probability for clinical trial success with smaller patient numbers in a shorter period of time. We propose to use multimodal imaging of αvβ3 integrin and oxidized collagen in mouse models of lung fibrosis to evaluate αvβ3 antagonism as a route to pathway-specific intervention. αvβ3 is implicated as a regulator of IPF development with αvβ3 expression elevated in preclinical models and in the lungs of IPF patients. Treatment with αvβ3 antagonists leads to reduction of lung fibrosis and enhanced survival in preclinical models of pulmonary fibrosis and several antagonists are entering clinical trials for IPF. The positron emission tomography (PET) probe 18F-FPP-RGD2 was used to image αvβ3 in (pre-)clinical studies of cancer. To assess disease activity, we’ve developed the allysine-binding magnetic resonance (MR) probe Gd-CHyd which reports on the oxidized collagen formed during fibrogenesis. We showed that imaging oxidized collagen predicts disease activity and treatment response. Because oxidized collagen is fundamental to fibrogenesis, Gd-CHyd can quantify pulmonary disease activity independent of cause and can be used generally to measure response to treatment. We will develop and optimize a multimodal 18F-FPP-RGD2 PET and Gd-CHyd MR imaging protocol in mouse models of pulmonary fibrosis, then use this to noninvasively quantify αvβ3 expression and fibrogenesis through the course of disease progression with validation by ex vivo measurements. We will then apply the protocol to confirm target engagement of an αvβ3 antagonist, determine optimal therapeutic dose, and use Gd-CHyd MR to measure therapeutic response. We hypothesize that molecular imaging will allow pre- clinical assessment of target relevance while simultaneously assessing disease activity and response to target inhibition, all of which will accelerate successful drug development for IPF.