PET imaging of radiation induced lung injury

项目摘要 2018年新增病例210万例，死亡180万例，肺癌是世界上最常见的癌症。 放射治疗是不能手术的非小细胞肺癌的标准护理，并赋予显著的 生存福利。不幸的是，放射治疗癌症的一个重要副作用是辐射诱发的肺。 损伤(RILI)-由于DNA损伤和自由基损伤以及随后的 肺暴露在电离辐射下引起的炎症反应。50%-76%的患者接受了 根据监测，肺癌的放射治疗每年都会出现某种形式的辐射损伤。 成像。RILI不仅是发病率和死亡率的重要来源，而且肺对辐射的敏感性 限制可用于治疗癌症的辐射量。RILI可分为两个阶段：1)急性 肺炎(辐射后1-6个月)引起肺部炎症和水肿，可能需要住院治疗 而且很少是致命的。2)慢性纤维化期(辐射后数月至数年)，在此期间阴燃 炎症导致纤维化组织取代正常肺组织，导致显著的发病率。目前， RILI的诊断基于临床病史、症状、肺功能检查和胸部影像。Rili通常是一种 诊断复发的恶性肿瘤和感染后的排斥反应已被排除，极少可能需要 侵入性肺组织活检以排除其他病因。充其量，我们可以使用当前的工具来诊断 RILI的存在，但我们无法：1)准确量化RILI的严重程度和分布 反复评估疾病的活动性和进展。这项提案旨在通过以下方式解决这些未得到满足的需求 1型胶原的非侵入性分子成像，这在活动性纤维化疾病中很常见，如RILI。 我们推测，一种新开发的正电子发射断层扫描探针68Ga-CBP8，目标是I型 胶原蛋白，将使RILI的早期检测和准确定量成为可能。我们进一步假设，使用 这种新的靶向成像方法将允许更好地预测疾病进展，从而最终帮助 确定哪些患者可以从早期治疗中受益。68Ga-CPB8与1型的亲和力和特异性 胶原蛋白已经被很好地建立，我们在特发性的成像中使用这种试剂有临床经验。 肺纤维化。在这里，我们第一次提出使用该试剂对放射性肺损伤进行成像。 该提案分为两个阶段。首先，我们的目标是确定68Ga-CPB8在 RILI区域和可用正电子发射计算机断层成像。接受过肺癌放射治疗的受试者 已知的RILI将在此概念验证目标中成像，结果将与高分辨率进行比较 计算机断层扫描(HRTC)图像。我们将在目前马萨诸塞州举行的IND下进行这项研究 综合医院。在第二阶段，胶原医疗公司将获得自己的IND，以进行一项更大规模的研究，患者 将在放射治疗前进行扫描，而不是在常规HRTC成像没有的情况下进行早期随访 准确。我们还旨在证明，正电子发射计算机断层扫描可以预测暴露于 胸部有辐射。

Project Summary With 2.1 million new cases in 2018, and 1.8 million deaths, lung cancer is the most common cancer in the world. Radiation therapy is the standard of care for inoperable non-small cell lung cancer and confers a significant survival benefit. Unfortunately, an important side effect of radiation therapy for cancer is Radiation Induced Lung Injury (RILI) - the direct tissue injury due to DNA damage and free radical injury, as well as the subsequent inflammatory response caused by exposure of the lungs to ionizing radiation. 50-76% of patients undergoing radiation therapy for lung cancer each year develop some form of radiation injury as seen on surveillance imaging. Not only is RILI a significant source of morbidity and mortality, but the lung’s sensitivity to radiation limits the amount of radiation which can be given to treat cancer. RILI can be divided into two phases: 1) Acute pneumonitis (1-6 months post-radiation) causing lung inflammation and edema which may require hospitalization and rarely is fatal. 2) Chronic fibrosis phase (months to years post radiation) during which smoldering inflammation causes fibrotic tissue to replace normal lung tissue and results in significant morbidity. Currently, RILI diagnosis is based on clinical history, symptoms, lung function tests, and chest imaging. RILI is typically a diagnosis of exclusion after recurrent malignancy and infection have been ruled out and rarely may require an invasive lung tissue biopsy to exclude alternative etiologies. At best, we can use the current tools to diagnose the presence of RILI, but we are unable to: 1) accurately quantify the severity and distribution of RILI 2) repeatedly assess disease activity and progression. This proposal aims to addresses these unmet needs through non-invasive molecular imaging of type 1 collagen, which is prevalent in active fibrotic disease such as RILI. We hypothesize that a newly developed positron emission tomography probe, 68Ga-CBP8, targeted to type I collagen, will enable earlier detection and accurate quantification of RILI. We further hypothesize that the use of this new targeted imaging approach will allow to better predict disease progression and thus ultimately help to identify which patients may benefit from early treatment. The affinity and specificity of 68Ga-CPB8 for type 1 collagen are well established and we have clinical experience with this agent in the imaging of idiopathic pulmonary fibrosis. Here, for the first time, we propose to use the agent to image radiation-induced lung injury. The proposal is divided into two phases. First, we aim to establish that 68Ga-CPB8 specifically accumulates in regions of RILI and can be imaged with PET. Subjects that underwent radiation therapy for lung cancer and are known to have RILI will be imaged in this proof-of-concept aim and results will be compared to high-resolution computed tomography (HRTC) images. We will conduct this study under a current IND held at Massachusetts General Hospital. In Phase 2, Collagen Medical will obtain its own IND to conduct a larger study where patients will be scanned prior to radiation therapy than followed up early when conventional HRTC imaging is not accurate. We also aim to demonstrate that PET imaging can predict disease progression after exposure to radiation in the chest area.