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（由申请人提供）：本提案的目标是将I型胶原特异性正电子发射断层扫描（PET）探针用于人体成像，并评估其用于患者肺纤维化直接成像的潜力。肺纤维化是肺瘢痕形成，其可由辐射损伤、药物毒性、环境原因（例如硅肺）或未知原因（即特发性肺纤维化（IPF））引起。尽管最近批准了两种治疗IPF的新药，但它仍然是一种致命的疾病，从诊断开始的平均生存期仅为2-3年。尽管这种快速的进展，疾病似乎是显着异质性在其临床过程和发病机制。目前的IPF成像是用高分辨率计算机断层扫描（HRCT）进行的，可以非侵入性地诊断IPF，但不能准确预测预后或对任何现有治疗的治疗反应。 在检测早期纤维化方面，纤维化的分子成像可能比HRCT更敏感，并且也可能能够区分新的活动性纤维化和稳定的疾病。一个敏感的测试，可以识别早期发病的纤维化可能有很大的效用，指导干预措施，以改变这种毁灭性的疾病的过程。基于成像活动性纤维化对患者进行分层的能力可以1）指导患者治疗，2）选择患者进行临床试验，以及3）监测治疗反应。在功能测试变化之前观察纤维化消退的能力将是监测新治疗方法疗效的有效手段。 本提案是对RFA-HL-16-001“肺部分子成像，第2阶段”的回应。在该RFA的第1阶段，我们制备了1型胶原靶向PET探针库，并在肺纤维化的博来霉素小鼠模型中对其进行筛选。我们鉴定了两种相似的探针，它们对肺纤维化显示出高特异性，并且其在肺中的摄取与胶原蛋白的增加相关。我们进一步表明，这些探针可用于监测第二种小鼠疾病模型的治疗反应。在这里，我们将通过进行临床前研究以支持IND申请，然后评估探针在健康志愿者中的药代动力学来开发这种用于人类的技术。为了验证探针，我们将对计划进行肺叶切除术的肺癌患者进行成像，并将探针摄取与组织学确定为纤维化的肺区域相关联。我们将开始通过对IPF患者进行成像并评估IPF患者中增加的探针摄取是否与更严重的疾病进展相关来实施该技术。这项为期3年的研究计划的成果将是一种胶原特异性PET探针，该探针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，以前瞻性地确定胶原蛋白特异性PET是否可以分层IPF患者，指导治疗计划，和/或监测治疗反应。IPF的临床病程非常不均匀，能够准确预测个体患者的病情是IPF患者护理和研究的迫切需求。(End摘要）