PET Imaging of Hypoxia with EF5

描述(由申请人提供)： 有许多临床研究直接证明了低氧在限制对基本上所有形式的癌症治疗的反应方面的重要性。此外，低氧被认为影响癌症的本质，低氧肿瘤更容易受到遗传不稳定和侵袭性表型的影响。目前，尚不清楚缺氧是否只是与侵袭性肿瘤有关，或者它是否是驱动力。通过非侵入性手段对临床相关的肿瘤缺氧进行成像的方法已经引起了人们的极大兴趣。在本申请中，我们将使用2-硝基咪唑缺氧标记物EF5来实现这一目的。EF5是独一无二的，因为它的氧依赖生物还原可以通过两种不同的方法进行研究：第一，高度特异的抗体可以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仪分析)；第二，使用F-18-1标记药物的非侵入性成像。在9L胶质肉瘤大鼠肿瘤模型中，这两种方法都被证明与个体肿瘤放射反应预测相关。使用这个模型，将检验三个假设(第四个将使用HTIOB0人肉瘤异种移植)：第一个目的将检验中到高浓度的低氧标志物对于促进组织低氧的最佳预测是必要的假设。这是我们先前赠款的延续，需要设计一种创新的方法(由芬兰的奥洛夫·索林博士开发)来生产高比活度的氟气(用正常技术是不可能的)。在这一目标下开发的技术将有利于计划中的人体研究，并允许使用放射性氟标记化合物的新方法。第二个目的是将现在验证的EF5的辐射反应预测与其他两项临床相关技术进行比较：摄取标记的铜-ATSM和间质液体压力。这个目标的目的是评估各种预测分析是否真的在监测缺氧或其他相关的耐药因素。第三个目标将检验临床上相关的假设，即F-18-EF5成像可以检测由于低氧空间分布的不均一性导致的肿瘤内辐射抵抗的变化。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一毫升左右的空间位置。我们的最终目标，将在HT1080人肉瘤移植瘤中进行研究，将检验F-18-EF5成像可以监测抗血管和抗血管生成治疗引起的微环境变化的假设。总而言之，这项资助的目的将扩大和提高我们在量化肿瘤微环境中临床相关缺氧程度和程度方面的总体实验室兴趣。

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.