Tumor Hypoxia Imaging - Laboratory and Clinical Studies

描述（由申请人提供）：我们的研究基于以下假设：肿瘤缺氧的有效非侵入性成像将改善癌症护理，并且更好地理解肿瘤缺氧图像的机制基础很重要。因此，我们建议在实验室和临床研究中开发和评估不同的无创缺氧成像方法。 在研究项目1（RP 1）中，我们将使用 异种移植模型，其含有缺氧诱导型报告基因，其表达可以通过光学和PET成像可视化。利用它，可以可视化初始缺氧诱导的分子事件及其空间分布，并与其他肿瘤缺氧替代物进行比较，例如下游基因的表达和外源性缺氧标记物的捕获。我们的目标是使用该模型作为工具来验证三种缺氧细胞标记物的使用：18F-FMISO，1241-IAZG和18F-EF 5。 在RP 2中，我们将评估几种NMR方法的有效性：T19 F-FMISO、DCE-MRI和乳酸盐测量，并与外源性缺氧标志物和pO 2探针数据的microPET成像进行比较。此外，将对NMR和microPET方法进行评价，以研究肿瘤缺氧的动力学，无论是内在的还是由干预引起的，例如辐射或抗血管生成治疗。 RP 3将验证一种放射基因治疗策略，以克服缺氧介导的放射抗性，结合缺氧成像，载体与放射增敏效应基因的传递，通过分子成像验证传递，以及通过放射根除肿瘤。我们将设计/构建表达缺氧诱导报告基因和拮抗DNA损伤修复的效应基因的载体，并产生复制缺陷型和条件复制型腺病毒。将在体外和体内研究腺病毒递送的功效和这些基因的放射增敏作用。最后，我们将定位异种移植物中的缺氧体积，在图像引导下递送腺病毒，并评估这种策略的有效性。 RP 4是一项临床PET/CT研究，测试1241-IAZG和18F-FMISO在结直肠癌和头颈癌中的作用。在第一个研究系列中，我们将在每个疾病部位约100名患者中进行两种示踪剂的头对头比较，以评估预后价值和图像质量，以便确定每个疾病部位的最佳示踪剂。在第二个研究系列中，将早期结直肠癌患者的缺氧图像与pO 2探针测量和内源性标志物的免疫组织化学进行比较。 我们相信，这一翻译研究计划，整合实验室和临床研究的一个重要问题，在癌症管理，最终将导致改善癌症治疗的结果。

DESCRIPTION (provided by applicant): Our research is based on the hypothesis that effective non-invasive imaging of tumor hypoxia will improve cancer care, and that it is important to better understand the mechanistic basis of tumor hypoxia images. Thus, we propose to develop and evaluate different non-invasive hypoxia imaging methods in laboratory and clinical studies. In Research Project 1 (RP1) we shall examine the biological underpinning of hypoxia imaging using a xenograft model that contains a hypoxia-inducible reporter gene, the expression of which can be visualized by optical and PET imaging. With it, the initial hypoxia-induced molecular event and its spatial distribution can be visualized and compared to other tumor hypoxia surrogates, e.g. expression of downstream genes and the trapping of exogenous hypoxia markers. Our goal is to use this model as a tool to validate the use of three hypoxic cell markers: 18F-FMISO, 1241-IAZG and 18F-EF5. In RP2 we shall assess the efficacy of several NMR approaches: T19F-FMISO, DCE-MRI and lactate measurement, in comparison with microPET imaging of exogenous hypoxia markers and pO2 probe data. In addition, both NMR and microPET methods will be evaluated for studies on the dynamics of tumor hypoxia, either intrinsic or resulting from intervention, e.g. radiation or anti-angiogenesis treatment. RP3 will validate a radio-gene therapy strategy to overcome hypoxia-mediated radioresistance, combining hypoxia imaging, delivery of vectors with a radiosensitizing effecter gene, verification of delivery by molecular imaging, and tumor eradication by radiation. We shall design/construct vectors that express a hypoxia-inducible reporter and an effecter gene that antagonizes DMA damage repair, and generate replication-defective and conditionally-replicative adenovirus. The efficacy of adenovirus delivery and the radiosensitizing effect of these genes will be studied in vitro and in vivo. Finally, we shall localize hypoxic volumes in xenografts, deliver the adenovirus under image guidance, and evaluate the efficacy of this strategy. RP4 is a clinical PET/CT study, testing 1241-IAZG and 18F-FMISO in colorectal and head/neck cancers. In the first study series we shall perform head-to-head comparison of the two tracers in -100 patients per disease site to evaluate both prognostic value and image quality, in order to identify the best tracer for each disease site. In the second study series, hypoxia images of patients with early colorectal cancers will be compared with pO2 probe measurement and immunohistochemistry of endogenous markers. We believe that this translation research program, integrating laboratory and clinical investigation on an important question in cancer management, will eventually lead to improvement in cancer treatment outcome.