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基础机制和过程的理解 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 可诱导的记者基因允许通过光学和核成像方法对缺氧诱导的分子事件级联反射。具体而言，在低氧响应元件的控制下，将与微膜响应元件的控制下，在微米响应元件的控制下，在微型响应元件的控制下，在微摄影元件的控制下，源自甲基丙氨酸激酶TK的表达（疱疹单纯疱疹病毒的融合基因和增强的绿色荧光蛋白EGFP）的肿瘤内分布将与微映射，数字自动摄影和荧光摄影。由于记者基因在HRE的控制之下，因此我们可以确定初始缺氧引起的事件的分布，并在肿瘤缺氧的生物学与其他缺氧相关的终点与替代物之间提供联系。具体而言，通过免疫组织化学（IHC）分析评估，将报告基因表达的分布与内源性（例如HIF-1Alpha和Ca9）和外源性（例如Pimonidazole和EF5）缺氧相关标记的分布进行比较。 此外，还将将记者基因表达的微型和放射自显影图与 在临床评估下的外源PET缺氧成像剂：18F-FMISO，18F-EF5和124I-IAZGP。在将缺氧诱导的分子事件与PET图像联系起来时，本研究提供了对非侵入性缺氧成像的首次直接验证。作为参考，我们将使用物理探针执行与图像在空间共同注册的肿瘤内PO-2测量值。然后，我们将采用这些技术来量化调节缺氧作用在内的干预措施的影响，包括辐射治疗后，包括碳原/高压氧呼吸以及重新氧。 最后，我们建议开发来自各种来源数据的空间共同注册的方法：PET，自显影和NMR图像，PO2探针数据，肿瘤组织学和内源性或外源标记的IHC分析，并认为来自互补方法的合并数据集将导致对综合性方法的共同数据集进行改进的肿瘤过氧化透明度的评估。