Multimodal quantitative PET/MR imaging of pulmonary fibrosis

肺纤维化的多模态定量 PET/MR 成像

• 批准号: 10477413
• 负责人: Eman Akam-Baxter
• 金额: $ 15.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477413
• 关键词: Address; Area; Binding; Biochemical; Biological; Biology; Bleomycin; Chemistry; Clinical; Clinical Trials; Collagen; Data; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Design; Drug Targeting; Early treatment; Fibrosis; Future; Image; Imaging Device; Immunohistochemistry; Inflammatory; Injections; Integrin alphaVbeta3; Integrins; Intervention; Knowledge; Lung; Lung diseases; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Modeling; Molecular Biology Techniques; Monitor; Multimodal Imaging; Mus; Natural History; Outcome; Output; Oxides; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Pirfenidone; Positron-Emission Tomography; Pre-Clinical Model; Probability; Progressive Disease; Protocols documentation; Pulmonary Fibrosis; Radiation; Reporting; Research; Research Project Grants; Resolution; Risk; Route; Signal Transduction; Stratification; Testing; Therapeutic; Time; Training; Validation; Work; antagonist; base; cost; disease heterogeneity; drug candidate; drug development; drug efficacy; fibrogenesis; high risk; idiopathic pulmonary fibrosis; imaging modality; imaging probe; improved; in vivo; indium-bleomycin; individual response; injured; lung imaging; lung injury; molecular imaging; mouse model; multimodality; nintedanib; non-invasive imaging; novel therapeutics; pre-clinical assessment; preclinical study; quantitative imaging; radiation-induced lung injury; response; skills; success; targeted treatment; tool; treatment response; uptake

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.

项目总结/摘要 特发性肺纤维化（IPF）是一种进展性疾病，中位生存期为2-4年 诊断后。经过30年的研究和20多项临床试验， IPF治疗：吡非尼酮和尼达尼布。虽然这两种药物都能减缓疾病进展， 个体IPF患者的治疗反应存在差异，两种药物均不能治愈，表明IPF 可能源于不同的病理途径，导致疾病异质性。IPF的药物开发 由于患者表型不佳以及缺乏评估疾病活动和早期治疗的工具， 反应因此，临床试验需要大量受试者来观察真实的疗效信号。 多模式分子成像可加速药物开发并最终改变IPF管理。 特定靶点的分子成像可以对受试者进行分层，评估药物-靶点结合并指导剂量 优化一种新的药物，设计结合到该目标。分子成像还可以评估疾病活动 并监测对治疗的反应因此，全面的多模态分子成像方案将改善 在更短的时间内以更少的患者数量成功进行临床试验的可能性。 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 评价αvβ3拮抗作用作为途径特异性干预的途径。αvβ3被认为是 在临床前模型和IPF患者的肺中，αvβ3表达升高的IPF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生存率 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（前）临床研究中，使用断层扫描（PET）探头18F-FPP-RGD 2对αvβ3进行成像。评估 疾病的活动，我们已经开发出的赖氨酸结合磁共振（MR）探针Gd-CHyd报告 在纤维形成过程中形成的氧化胶原蛋白上。我们发现氧化胶原蛋白成像可以预测 疾病活动和治疗反应。由于氧化胶原是纤维形成的基础， 可以量化独立于病因的肺部疾病活动， 接受治疗我们将开发和优化多模式18F-FPP-RGD 2 PET和Gd-CHyd MR成像 在小鼠肺纤维化模型中，然后使用该方法非侵入性地定量αvβ3表达， 通过离体测量验证的疾病进展过程中的纤维化。然后我们将 应用该方案以确认αvβ3拮抗剂的靶向结合，确定最佳治疗剂量， 并使用Gd-CHyd MR测量治疗反应。我们假设分子成像将允许预- 临床评估靶点相关性，同时评估疾病活动性和对靶点的反应 所有这些都将加速成功开发治疗IPF的药物。