Nuclear Magnetic Resonance Imaging of Tumor Hypoxia

肿瘤缺氧的核磁共振成像

• 批准号: 7102436
• 负责人: JASON Arthur KOUTCHER
• 金额: $ 20.32万
• 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/7102436
• 关键词: hypoxia; magnetic resonance imaging; neoplasm /cancer; suicide

Treatment strategies are stratified by risk factors; a goal of stratification into different prognostic groups is to design risk based treatment strategies. Long term survival is determined by "risk factors" that predict prognostic parameters such as probability of local control and risk of developing systemic or metastatic disease. Tumor hypoxia is predictive of both risk of metastases and aggressive local disease. A non-invasive assay to measure hypoxia would provide prognostic information regarding local tumor aggressiveness and metastatic risk for development of risk based therapy, and for monitoring changes in oxygenation with treatment, could impact further therapy. The central hypothesis of this proposal is that tumor hypoxia and changes in oxygenation can be evaluated non-invasively using selected surrogate "markers". In all studies, we will utilize a stereotaxic template we have developed to register both the in vivo data and the p02 and pimonidazole studies. In Aim 1 we will test and validate a novel derivative of misonidazole (trifluoromisonidazole (T19F-FMISO)) for imaging hypoxia. We will determine the optimal dose as a balance between signal to noise requirements vs. specificity for imaging hypoxia, and also compare to 18F-misonidazole and p02. In Aim 2 we will evaluate quantitation of lactate, dynamic contrast enhanced MRI, andT19F-FMISO as oxygen surrogates and validate them against p02 and pimonidazole. In Aim 2B, we will study changes in hypoxia induced by anti-neoplastic therapy and use these measurements as potential surrogate and compare to p02, microvessel density and radiobiological assays. The goal of Aim 2 is to determine which is the best surrogate of hypoxia and apply this in Aim 3. Aim 3 will use this data to optimize hypoxia driven suicide gene therapy. In aim 3, we will develop a fusion suicide gene (Cytosine Deaminase - Uracil Phosphoribosyl Transferase - CD-UPRT), under the control of a hypoxia response element (HRE) which can be quantitatively imaged by 19F NMR chemical shift imaging. We will develop this system as a both a reporter and suicide therapy system and evaluate its efficacy and compare it with thymidine kinase in parallel studies.

治疗策略按危险因素分层；分层为不同预后组的目标是 设计基于风险的治疗策略。长期生存由预测的“风险因素”决定 预后参数，例如局部控制的概率和发生全身性或转移性的风险 疾病。肿瘤缺氧可预测转移风险和侵袭性局部疾病。一个 测量缺氧的非侵入性测定将提供有关局部肿瘤的预后信息 开发基于风险的治疗的侵袭性和转移风险，以及监测变化 治疗过程中的氧合可能会影响进一步的治疗。该提案的中心假设是 肿瘤缺氧和氧合变化可以使用选定的替代物进行非侵入性评估 “标记”。在所有研究中，我们将利用我们开发的立体定位模板来注册 体内数据以及 p02 和哌莫硝唑研究。在目标 1 中，我们将测试并验证 米索硝唑（三氟米索硝唑（T19F-FMISO））用于缺氧成像。我们将确定最优的 剂量作为信噪比要求与缺氧成像特异性之间的平衡，并且 与18F-米索硝唑和p02相比。在目标 2 中，我们将评估乳酸定量、动态对比 增强 MRI 和 T19F-FMISO 作为氧替代物，并针对 p02 和哌莫硝唑验证它们。 在目标2B中，我们将研究抗肿瘤治疗引起的缺氧变化，并利用这些变化 测量作为潜在的替代物，并与 pO2、微血管密度和放射生物学测定进行比较。 目标 2 的目标是确定哪个是缺氧的最佳替代方案，并将其应用于目标 3。目标 3 将 利用这些数据来优化缺氧驱动的自杀基因疗法。在目标3中，我们将开发一种融合自杀 基因（胞嘧啶脱氨酶 - 尿嘧啶磷酸核糖基转移酶 - CD-UPRT），在 a 的控制下 缺氧反应元件（HRE），可通过 19F NMR 化学位移成像进行定量成像。 我们将开发该系统作为报告者和自杀治疗系统，并评估其功效和 在平行研究中将其与胸苷激酶进行比较。