Quantitative MRI Assessment of Tumor Vascular and Oxygen Reactivity

描述（由申请人提供）：人们普遍认为，缺氧是控制肿瘤侵袭性的重要因素，缺氧组织对常规治疗更具抗性。肿瘤氧合的非侵入性定量成像可以改善癌症患者的临床管理和治疗，特别是考虑到最近对血管生成抑制剂和氧增强剂的临床测试。因此，本申请的长期目标是开发用于表征肿瘤氧合状态的定量MRI方法，并评价其作为肿瘤缺氧和治疗反应的潜在替代生物标志物的作用。该提议的一般假设是i）将造影剂的作用与血氧水平依赖性（BOLD）测量结合联合收割机的MRI方法可以可靠地用于监测肿瘤氧变化，ii）血容量的评估，最大氧饱和度扰动之后的血管反应性和氧调节可用于区分常氧组织和缺氧组织，以及iii）对比增强的BOLD MRI可用于改善抗血管生成剂和放射疗法的治疗安排。提出的研究重点是开发和验证一种对比增强的BOLD方法，该方法有可能分离和量化肿瘤血管反应性和氧调节。我们将评估并纳入局部组织pH值和红细胞压积对这些测量值影响的校正（目的1）。对比增强BOLD参数和肿瘤缺氧的验证将通过与组织学和PET剂[18 F]氟咪唑（FMISO）的摄取进行比较来实现（目的2）。最后，BOLD参数将应用于小鼠癌症模型中，以计划和监测抗血管生成剂、氧增强剂和放射治疗的反应（目标3）。重要性：一旦开发和验证，这些新方法将提供定量工具，用于改善临床管理和测量新的抗血管生成和/或氧增强治疗的功效。人们普遍认为，低氧或缺氧会增加肿瘤的侵袭性并降低常规治疗的有效性。可以识别具有缺氧区域的肿瘤并监测肿瘤氧合变化的成像方法可能会改善癌症患者的临床管理和治疗，特别是考虑到最近对旨在改善肿瘤氧合的药物进行的临床测试。本申请中描述的研究的目标是开发这些成像方法，并通过监测动物癌症模型对常规治疗的反应和靶向低氧肿瘤的有前景的新药物来证明其临床相关性。

DESCRIPTION (provided by applicant): It is widely accepted that hypoxia is an important factor governing the aggressiveness of tumors and that hypoxic tissue is more resistant to conventional therapeutics. Non-invasive quantitative imaging of tumor oxygenation could lead to improved clinical management and treatment of cancer patients, especially considering the recent clinical testing of angiogenesis inhibitors and oxygen-enhancing agents. Therefore, the long-term goal of this application is to develop quantitative MRI methods for the characterization of tumor oxygenation status and to evaluate its role as a potential surrogate biomarker of tumor hypoxia and treatment response. The general hypotheses for this proposal are i) MRI methods that combine the effects of contrast agents with blood oxygenation level dependent (BOLD) measurements can reliably be used to monitor tumor oxygen variations, ii) the assessment of blood volume, vascular reactivity and oxygen modulation following a maximal oxygen saturation perturbation can be used to differentiate between normoxic and hypoxic tissue and iii) contrast enhanced BOLD MRI can be used to improve treatment scheduling of anti-angiogenic agents and radiation therapy. The studies proposed focus on the development and validation of a contrast enhanced BOLD method that has the potential to separate and quantify tumor vascular reactivity and oxygen modulation. We will evaluate and incorporate corrections for the influence of local tissue pH and hematocrit on these measurements (Aim 1). The validation of the contrast enhanced BOLD parameters and tumor hypoxia will be achieved by comparison to histology and the uptake of the PET agent [18F]fluoromisonidazole (FMISO) (Aim 2). Finally, the BOLD parameters will be applied in a mouse model of cancer to plan and monitor the response of anti-angiogenic agents, oxygen-enhancing agents and radiotherapy (Aim 3). Significance: Once developed and validated these new methods will provide quantitative tools for improving clinical management and for measuring the efficacies of new anti-angiogenic and/or oxygen-enhancing treatments. It is widely accepted that low oxygenation, or hypoxia, increases the aggressiveness of tumors and decreases the effectiveness of conventional therapeutics. Imaging methods that can identify tumors with hypoxic regions and monitor changes in tumor oxygenation could lead to improved clinical management and treatment of cancer patients, especially considering the recent clinical testing of agents designed to improve tumor oxygenation. The goal of the study described in this application is to develop these imaging methods and demonstrate their clinical relevance by monitoring the response of animal cancer models to conventional treatment and promising new agents targeting hypoxic tumors.