PET Imaging of Hypoxia with EF5

使用 EF5 进行缺氧 PET 成像

• 批准号: 7354103
• 负责人: CAMERON J KOCH
• 金额: $ 34.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354103
• 关键词: Affect; Angiogenesis Inhibitors; Animal Model; Animals; Antibodies; Binding; Biochemistry; Biological Assay; Biopsy; Blood flow; Cells; Clinical Research; Data; Detection; Development; Drug Kinetics; EF5; Electrodes; Engineering; FMISO; Face; Finland; Fluorescence Microscopy; Fluorides; Fluorine; Gases; Genes; Genetic; Goals; Grant; Heterogeneity; Homologous Gene; Human; Hypoxia; Image; In Situ; Individual; Institution; Intensity-Modulated Radiotherapy; Intercellular Fluid; Intermediate Filament Proteins; Invasive; Label; Laboratories; Lead; Location; Malignant Neoplasms; Measures; Metals; Methods; Modality; Modeling; Molecular Biology; Monitor; Nature; Needles; Normal tissue morphology; Nude Rats; Numbers; Oxygen; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Positron-Emission Tomography; Prediction of Radiation Response; Property; Proteins; Purpose; Radiation; Radioactive; Rattus; Research; Research Personnel; Resistance; Resolution; Role; Signal Transduction; Spatial Distribution; Techniques; Technology; Technology Transfer; Testing; Thinking; Tissue Sample; Tissues; Validation; Variant; Vascular blood supply; Xenograft procedure; antiangiogenesis therapy; azomycin; base; cancer therapy; clinically relevant; copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); driving force; gliosarcoma; human study; innovation; interest; method development; pressure; programs; proton beam; radiation resistance; resistance factors; response; sarcoma; success; time interval; tissue oxygenation; tumor; uptake

DESCRIPTION (provided by applicant): There are many clinical studies directly demonstrating the importance of hypoxia in limiting the response to essentially all forms of cancer therapy. Additionally, hypoxia is thought to affect the very nature of cancer, with hypoxic tumors being more susceptible to genetic instability and aggressive phenotypes. At present, it is not known whether hypoxia is simply associated with aggressive tumors, or whether it is the driving force. There has been a great interest in the development of methods to image clinically relevant tumor hypoxia by non-invasive means. In this Application we will employ a 2-nitroimidazole hypoxia marker, EF5, for this purpose. EF5 is unique because its oxygen-dependent bioreduction can be studied in two distinct ways: first; highly specific antibodies can be used for quantitative immunohistochemical detection at sub-cellular resolution (e.g. fluorescence microscopy of tissue sections or flow cytometric analysis) and secondly; non-invasive imaging using F-18-1abeled drug. Both methods have been shown to correlate with individual-tumor radiation-response prediction in the 9L gliosarcoma rat-tumor-model. Using this model, three hypotheses will be tested (a fourth will employ the HTIOB0 human sarcoma xenograft): The first aim will test the hypothesis that moderate to high concentrations of hypoxia markers are necessary to promote optimal prediction of tissue hypoxia. This represents a continuation of our prior grant and requires the engineering of an innovative method (developed by Dr. Olof Solin in Finland) to produce high specific activity fluorine gas (not possible with normal techniques). The technology developed in this aim will benefit planned human studies, and allow new methods for labeling compounds with radioactive fluorine. The second Aim will compare the now validated radiation response prediction of EF5 with two other clinically relevant techniques: uptake of labeled Cu-ATSM and interstitial fluid pressure. The goal in this aim is to assess whether the various predictive assays are truly monitoring hypoxia, or other relevant resistance factors. The 3rd Aim will test the clinically relevant hypothesis that F-18-EF5 imaging can detect intra-tumoral changes in radiation resistance caused by heterogeneity in the spatial distribution of hypoxia. Success of this Aim could lead to important new uses of therapies such as IMRT and proton beams which can be directed to spatial locations of one cc or so. Our final Aim, to be studied in the HT1080 human sarcoma xenograft, will test the hypothesis that F-18-EF5 imaging can monitor microenvironmental changes caused by antivascular and antiangiogenic therapies. In summary, the aims of this grant will extend and advance our overall laboratory interest in quantifying the degree and extent of clinically relevant hypoxia in the tumor microenvironment.

描述（由申请人提供）： 许多临床研究直接证明了缺氧在限制几乎所有形式的癌症治疗反应方面的重要性。此外，缺氧被认为会影响癌症的本质，缺氧肿瘤更容易受到遗传不稳定和侵袭性表型的影响。目前，尚不清楚缺氧是否仅仅与侵袭性肿瘤有关，或者是否是其驱动力。人们对开发通过非侵入性手段对临床相关肿瘤缺氧进行成像的方法产生了极大的兴趣。在此应用中，我们将使用 2-硝基咪唑缺氧标记物 EF5 来实现此目的。 EF5 是独一无二的，因为它的氧依赖性生物还原可以通过两种不同的方式进行研究：第一；高度特异性的抗体可用于亚细胞分辨率的定量免疫组织化学检测（例如组织切片的荧光显微镜或流式细胞术分析）；其次；使用 F-18-1 标记药物进行非侵入性成像。这两种方法均已被证明与 9L 胶质肉瘤大鼠肿瘤模型中的个体肿瘤辐射反应预测相关。使用该模型，将测试三个假设（第四个假设将采用 HTIOB0 人类肉瘤异种移植物）：第一个目标将测试以下假设：中等到高浓度的缺氧标记物对于促进组织缺氧的最佳预测是必要的。这代表了我们先前资助的延续，并需要设计一种创新方法（由芬兰的 Olof Solin 博士开发）来生产高比活度氟气（常规技术不可能实现）。为此开发的技术将有利于计划中的人体研究，并提供用放射性氟标记化合物的新方法。第二个目标将比较现已验证的 EF5 辐射响应预测与其他两种临床相关技术：标记 Cu-ATSM 的摄取和间质液压力。该目的的目的是评估各种预测分析是否真正监测缺氧或其他相关阻力因素。第三个目标将检验临床相关的假设，即 F-18-EF5 成像可以检测肿瘤内由缺氧空间分布的异质性引起的抗辐射变化。这一目标的成功可能会导致 IMRT 和质子束等疗法的重要新用途，这些疗法可以定向到 1 cc 左右的空间位置。我们的最终目标是在 HT1080 人类肉瘤异种移植物中进行研究，将检验 F-18-EF5 成像可以监测抗血管和抗血管生成疗法引起的微环境变化的假设。总之，这笔赠款的目的将扩展和推进我们实验室对量化肿瘤微环境中临床相关缺氧程度和范围的总体兴趣。