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.

该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 用核方法获得的缺氧图像。为了实现这一目标，我们将使用含有缺氧的肿瘤模型 诱导型报告基因，允许通过光学和核成像方法侵入性或非侵入性地观察缺氧诱导的分子事件级联。具体而言，报告基因构建体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）的表达在缺氧反应元件HRE的控制下的肿瘤内分布将使用 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 控制，因此我们可以确定初始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指标之间的联系。具体而言，报告基因表达的分布将与内源性（例如 HIF-1α 和 Ca9）和外源性（例如哌莫硝唑和 EF5）缺氧相关标记物的模式进行比较，通过免疫组织化学 (IHC) 分析进行评估， 此外，报告基因表达的 microPET 和放射自显影图像也将与 正在临床评估的外源性PET缺氧显像剂：18F-FMISO、18F-EF5和124I-IAZGP。通过将缺氧诱导的分子事件与 PET 图像联系起来，这项研究首次对非侵入性缺氧成像进行了直接验证。作为参考，我们将使用物理探针进行肿瘤内 pO-2 测量，这些测量与图像在空间上共同配准。然后，我们将应用这些技术来量化调节缺氧影响的干预措施的效果，包括卡波根/高压氧呼吸以及放射治疗后的再氧合。 最后，我们建议开发各种来源的数据空间共同配准的方法：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，相信来自互补的组合数据集方法将改进对肿瘤缺氧的评估。