Tumor Hypoxia Imaging - Laboratory and Clinical Studies

描述(申请人提供)：我们的研究是基于这样一个假设，即有效的肿瘤乏氧无创成像将改善癌症治疗，而且更好地了解肿瘤乏氧图像的机制基础是重要的。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低氧成像方法。 在研究项目1(RP1)中，我们将使用一种 异种移植模型，含有低氧诱导的报告基因，其表达可通过光学和PET成像进行可视化。利用它，可以可视化最初的低氧诱导的分子事件及其空间分布，并与其他肿瘤低氧替代物进行比较，例如下游基因的表达和外源性低氧标志物的捕获。我们的目标是利用这个模型作为一个工具来验证三种低氧细胞标志物的使用：18F-FMISO，1241-IAZG和18F-EF5。 在RP2中，我们将评估几种核磁共振方法的有效性：T19F-FMISO、DCE-MRI和乳酸测量，并与外源性低氧标志物和pO2探针数据的microPET成像进行比较。此外，核磁共振和microPET方法都将被用于研究肿瘤缺氧的动力学，无论是内在的还是由干预引起的，例如放射治疗或抗血管生成治疗。 RP3将验证一种克服低氧介导的辐射抵抗的放射基因治疗策略，将低氧成像、携带辐射增敏效应基因的载体传递、通过分子成像验证传递以及通过辐射根除肿瘤相结合。我们将设计/构建表达低氧诱导的报告基因和拮抗DMA损伤修复的效应基因的载体，并产生复制缺陷和条件复制型腺病毒。腺病毒的有效性和这些基因的辐射增敏作用将在体外和体内进行研究。最后，我们将定位异种移植物中的缺氧量，在影像引导下递送腺病毒，并评估这一策略的效果。 RP4是一项临床PET/CT研究，在结直肠癌和头颈癌中检测1241-IAZG和18F-FMISO。在第一个研究系列中，我们将对每个疾病部位的100名患者进行两种示踪剂的面对面比较，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，早期结直肠癌患者的缺氧图像将与PO2探头测量和内源性标志物的免疫组织化学进行比较。 我们相信，这个将实验室和临床研究结合在一起的翻译研究计划，对癌症管理中的一个重要问题的研究，最终将导致癌症治疗结果的改善。

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.