Detection of Tumor Hypoxia by Non-invasive Nuclear Imaging Methods

无创核成像方法检测肿瘤缺氧

• 批准号: 7102435
• 负责人: JOHN L HUMM
• 金额: $ 14.82万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102435
• 关键词: hypoxia; neoplasm /cancer; reporter genes

The overall goal of this project is to improve our understanding of the mechanisms and processes underlying tumor hypoxia images obtained with nuclear methods. Towards this goal, we shall use tumor models that contain a hypoxia inducible reporter gene to allow the cascade of molecular events induced by hypoxia to be either invasively or non-invasively visualized by optical and nuclear imaging methods. Specifically, the intra-tumor distribution of the expression of the reporter gene construct HRE-tkeGFP (the fusion gene of the herpes simplex virus type 1 thymidine kinase tk and the enhanced green fluorescence protein eGFP), under the control of the hypoxia responsive element HRE will be imaged with microPET, digital autoradiography and fluorescence microscopy. Because the reporter gene is under the control of the HRE, we can determine the distribution of the initial hypoxia-induced event and provide a link between the biology of tumor hypoxia and other hypoxia-associated endpoints and surrogates. Specifically, the distributions of reporter gene expression will be compared with patterns of endogenous (e.g. HIF-1alpha and Ca9) and exogenous (e.g. pimonidazole and EF5) hypoxia-associated markers, as assessed by immunohistochemical (IHC) analysis, In addition, microPET and autoradiography images of reporter gene expression will also be compared to the images of exogenous PET hypoxia imaging agents that are under clinical evaluation: 18F-FMISO, 18F-EF5 and 124I-IAZGP. In linking hypoxia-induced molecular events to PET images, this study provides the first direct validation of non-invasive hypoxia imaging. As a reference, we shall use physical probes to perform intra-tumoral pO-2 measurements that are spatially co-registered with the images. We shall then apply these techniques to quantify the effect of interventions that modulate the effects of hypoxia including carbogen/hyperbaric oxygen breathing as well as re-oxygenation following radiation treatment. Finally, we propose to develop methods for spatial co-registration of the data from various sources: PET, autoradiography and NMR images, pO2 probe data, tumor histology and IHC analysis of endogenous or exogenous markers, with the belief that the combined datasets from complementary methods will lead to an improved assessment of tumor hypoxia.

这个项目的总体目标是提高我们对肿瘤潜在机制和过程的理解。 核方法获得的低氧图像。为了达到这个目标，我们将使用包含低氧的肿瘤模型 可诱导的报告基因，允许通过光学和核成像方法以侵入性或非侵入性的方式显示由低氧引起的分子事件级联。具体地说，在缺氧反应元件HRE的控制下，报告基因构建HRE-tkeGFP(单纯疱疹病毒1型胸苷激酶tk和增强型绿色荧光蛋白EGFP的融合基因)在肿瘤内的表达分布将用microPET、数字放射自显影和荧光显微镜进行成像。由于报告基因受HRE的控制，我们可以确定最初缺氧诱导事件的分布，并提供肿瘤缺氧生物学与其他缺氧相关终点和替代物之间的联系。具体地说，报告基因表达的分布将与内源性(例如HIF-1α和Ca9)和外源性(例如匹莫硝唑和EF5)低氧相关标志物的模式进行比较，如免疫组织化学(IHC)分析所评估的， 此外，报告基因表达的microPET和放射自显影图像也将与 正在接受临床评估的外源性PET乏氧显像剂：18F-FMISO、18F-EF5和124I-IAZGP。在将低氧诱导的分子事件与PET图像联系起来的过程中，这项研究首次直接验证了非侵入性低氧成像。作为参考，我们将使用物理探针来执行与图像空间配准的肿瘤内Po-2测量。然后，我们将应用这些技术来量化调节低氧影响的干预措施的效果，包括碳氧/高压氧呼吸以及放射治疗后的复氧。 最后，我们建议开发不同来源的数据的空间联合配准方法：PET、放射自显影和核磁共振图像、pO2探针数据、肿瘤组织学和内源性或外源性标记物的IHC分析，相信来自互补方法的组合数据集将导致对肿瘤缺氧的更好的评估。