PET Imaging of Pulmonary Fibrosis

肺纤维化的 PET 成像

• 批准号: 9090458
• 负责人: Peter D Caravan
• 金额: $ 76.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090458
• 关键词: Animal Model; Animals; Asbestosis; Biological; Breathing; Cancer Patient; Cessation of life; Cicatrix; Clinic; Clinical; Clinical Data; Clinical Trials; Collagen; Collagen Fibril; Collagen Type I; Deposition; Diagnosis; Disease; Disease Progression; Drug Kinetics; Drug toxicity; Fibrosis; Goals; Hamman-Rich syndrome; High Resolution Computed Tomography; Histologic; Histology; Human; Human Volunteers; Image; Imaging technology; Intervention; Investigational Drugs; Investigational New Drug Application; Libraries; Lobectomy; Lung; Malignant neoplasm of lung; Measurement; Measures; Monitor; Operative Surgical Procedures; Outcome; Pathogenesis; Patient Care; Patient Schedules; Patients; Phase; Positron; Positron-Emission Tomography; Prior Chemotherapy; Production; Progressive Disease; Pulmonary Fibrosis; Radiation Fibrosis; Radiation Injuries; Radiation therapy; Radiometry; Recruitment Activity; Research; Resected; Safety; Scanning; Schedule; Signal Transduction; Silicosis; Specificity; Stable Disease; Technology; Testing; Time; Tissues; Toxic effect; Translating; abstracting; analytical method; base; cancer surgery; early onset; fibrogenesis; healthy volunteer; imaging probe; indium-bleomycin; individual patient; manufacturing process; molecular imaging; mouse model; novel therapeutic intervention; novel therapeutics; outcome forecast; patient stratification; pre-clinical; preclinical study; response; treatment planning; treatment response; uptake

 DESCRIPTION (provided by applicant): The goal of this proposal is to translate a type I collagen-specific positron emission tomography (PET) probe for human imaging and to assess its potential for direct imaging of pulmonary fibrosis in patients. Pulmonary fibrosis is a scarrin of the lungs that can arise from radiation injury, drug toxicity, environmental causes (e.g. silicosis) or from unknown cause, i.e. idiopathic pulmonary fibrosis (IPF). Despite the recent approval of two new drugs to treat IPF, it remains a deadly disease where average survival from time of diagnosis is only 2-3 years overall. Despite this rapid progression, the disease appears to be markedly heterogeneous both in its clinical course and pathogenesis. Current IPF imaging is carried out with high resolution computed tomography (HRCT) scanning, which may diagnose IPF non-invasively, however it cannot accurately predict prognosis or therapy response to any of the currently available treatments. Molecular imaging of fibrosis may be more sensitive than HRCT in detecting early fibrosis, and may also be able to distinguish new, active fibrosis from stable disease. A sensitive test that can identify early onset of fibrosis may have great utility i guiding interventions to alter the course of this devastating disease. The ability to stratify patients based on imaging active fibrosis could 1) guide patient therapy, 2) select patients for clinical trials, and 3) monitor for treatment response. The ability to see fibrosis regression prio to changes in functional tests would be an effective means to monitor the efficacy new therapeutic approaches. This proposal is in response to RFA-HL-16-001, "Molecular Imaging of the Lung, Phase 2". In Phase 1 of this RFA we prepared a library of type 1 collagen targeted PET probes and screened them in the bleomycin mouse model of pulmonary fibrosis. We identified two similar probes that showed high specificity for pulmonary fibrosis and whose uptake in the lung correlated with increased collagen. We further showed that these probes could be used to monitor treatment response in a second mouse model of disease. Here, we will develop this technology for human use by performing preclinical studies to support an IND filing, and then evaluating the pharmacokinetics of the probe in healthy volunteers. To validate the probe, we will image lung cancer patients scheduled for lobectomy and correlate probe uptake with regions of lung histologically determined to be fibrotic. We will begin to implement this technology by imaging IPF patients and assessing whether increased probe uptake in IPF patients correlates with more progressive disease. The outcome of this 3-year research plan will be a collagen-specific PET probe that has been validated in patients with known pulmonary fibrosis. This research would enable further, larger trials to prospectively determine whether collagen-specific PET can stratify IPF patients, guide treatment planning, and/or monitor treatment response. The clinical course of IPF is very heterogeneous, and being able to accurately predict the prognoses of individual patients is a pressing need in both IPF patient care and research. (End of Abstract)

 描述（由适用提供）：该提案的目的是翻译I型胶原特异性的正电子发射断层扫描（PET）探针，以进行人体成像，并评估其直接成像患者肺纤维化的可能性。肺纤维化是肺的疤痕，可能是由于放射线损伤，药物毒性，环境原因（例如硅化）或未知原因，即特发性肺纤维化（IPF）引起的。尽管最近获得了两种新药物来治疗IPF，但它仍然是一种致命的疾病，即诊断时间的平均生存率总计仅2 - 3年。尽管发展了这种迅速的进展，但在其临床病程和发病机理中，该疾病似乎都是明显异质的。当前的IPF成像是通过高分辨率计算机断层扫描（HRCT）扫描进行的，该扫描可能非侵入性地诊断IPF，但是它不能进行敏感的测试，该测试可以鉴定出早期纤维化的早期发作可能具有很大的效用I指导干预措施以改变这种毁灭性疾病的病程。根据成像活性纤维化对患者进行分层的能力可以指导患者治疗，2）选择患者进行临床试验，3）监测治疗反应。看到纤维化回归对功能测试变化的能力将是监测有效性新疗法方法的有效手段。该建议是对RFA-HL-16-001的响应，“肺的分子成像，第2阶段”。在此RFA的第1阶段，我们准备了一个1型胶原蛋白靶向PET探针的库，并筛选了它们，我们发现了两个相似的问题，这些问题表现出对肺纤维化的高特异性，并且在肺中的摄取与胶原蛋白的增加相关。我们进一步表明，这些问题可用于监测第二种小鼠疾病模型中的治疗反应。在这里，我们将通过进行临床前研究来支持IND归档，然后评估健康志愿者中探针的药代动力学，从而开发这种技术供人类使用。为了验证探针，我们将对安排进行肺切除术的肺癌患者成像，并将探针摄取与肺部组织学区域确定为纤维化。我们将开始通过对IPF患者进行成像并评估IPF患者的探测吸收是否与更多进行性疾病相关的探针吸收是否与更多的探针进行实施。该为期3年的研究计划的结果将是一种胶原蛋白特异性的PET探测，已在已知肺纤维化患者中得到验证。这项研究将使进一步的更大的试验前瞻性地确定胶原蛋白特异性PET是否可以对IPF患者进行分层，指导治疗计划和/或监测治疗反应。 IPF的临床过程非常异构，并且能够准确预测个别患者的预后是IPF患者护理和研究的紧迫需求。 （抽象的结尾）