PET Imaging of Pulmonary Fibrosis

 描述(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，并评估其对患者肺纤维化直接成像的潜力。肺纤维化是由辐射损伤、药物中毒、环境因素(如矽肺)或不明原因如特发性肺纤维化(IPF)引起的肺部红斑症。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，总体来说，从诊断开始的平均生存期只有2-3年。尽管进展如此迅速，但该病在临床过程和发病机制上似乎都具有明显的异质性。目前的IPF成像是通过高分辨率计算机断层扫描(HRCT)进行的，它可以无创性地诊断IPF，但不能准确地预测预后或对目前可用的治疗方法的疗效。在发现早期纤维化方面，纤维化的分子成像可能比HRCT更敏感，也可能能够区分新的活动性纤维化和稳定期疾病。一项可以识别早期纤维化的敏感测试可能会对指导干预改变这种毁灭性疾病的进程有很大的帮助。根据影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。能够看到纤维化回归PRIO到功能试验的变化，将是监测疗效的有效手段，新的治疗方法。这项提议是对RFA-HL-16-001，“肺的分子成像，第二阶段”的响应。在此RFA的第一阶段，我们制备了1型胶原靶向PET探针库，并在博莱霉素肺纤维化小鼠模型中对它们进行了筛选。我们确定了两个类似的探针，它们对肺纤维化显示出高度的特异性，其在肺中的摄取与胶原蛋白的增加相关。我们进一步证明，这些探针可以用于监测第二种疾病小鼠模型的治疗反应。在这里，我们将开发这项技术供人类使用，方法是进行临床前研究以支持IND备案，然后评估该探针在健康志愿者中的药代动力学。为了验证探针的有效性，我们将对计划进行肺叶切除术的肺癌患者进行成像，并将探针摄取与肺组织学确定为纤维化的区域相关联。我们将开始实施这项技术，方法是对IPF患者进行成像，并评估IPF患者摄取的探针增加是否与疾病进展相关。这项为期3年的研究计划的结果将是一种已在已知肺纤维化患者中得到验证的胶原蛋白特异性PET探针。这项研究将使进一步的更大规模的试验能够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的临床病程具有很强的异质性，能够准确预测个体患者的预后是IPF患者护理和研究的迫切需要。(摘要结束)

 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)