Quantitative MRI Assessment of Tumor Hypoxia and Angiogenesis

人们普遍认为，缺氧和血管生成是影响血管侵袭性的重要因素。 肿瘤。这些特征的非侵入性定量成像可以改善临床管理和 癌症患者的治疗，特别是考虑到最近在临床应用的进展 血管生成抑制剂和氧气增强剂。因此，此应用程序的长期目标是 建立定量的MRI方法来表征肿瘤血管的形态、功能和 氧合状态及其作为缺氧和治疗潜在替代生物标志物的作用 回应。这一建议的一般假设是：1)结合对比效果的磁共振成像方法 具有血氧水平依赖(BOLD)测量的试剂可以可靠地用于监测肿瘤 氧变化，ii)动态磁化率对比(DSC)-红细胞(RBC)流动的MRI测量和 与血浆血流动力学相比，分布将更好地描绘血管生理异常区域 参数，以及iii)肿瘤微环境的多参数MRI评估可以区分 常氧组织和低氧组织之间。建议的研究重点是开发和验证一个 有可能分离和量化肿瘤血管反应性的对比增强BOLD方法 以及氧气调节的影响。我们将评估并纳入对当地影响的修正 组织pH值和红细胞压积的测量，并评估这种方法的有效性，以跟踪 随治疗而改变(目标1)。拟议的DSC-MRI研究将开发方案和造影剂来 评估肿瘤中红细胞(RBC)的流量、体积和平均通过时间，并进行比较和对比 对那些来自血浆分布造影剂的措施(目标2)。BOLD和DSC-MRI 然后将参数与从扩散加权(DW)得出的其他生理测量相结合 核磁共振和正电子发射计算机断层扫描，以提供驱动的潜在机制的定量评估 肿瘤缺氧的发展(目标3)。意义：一旦开发和验证，这些新方法将 为改进临床管理和测量新的抗血管生成药物的有效性提供量化工具 和/或氧气增强治疗。

It is widely accepted that hypoxia and angiogenesis are important factors governing the aggressiveness of tumors. Non-invasive quantitative imaging of these features could lead to improved clinical management and treatment of cancer patients, especially considering recent advances in the clinical application 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 vascular morphology, function and oxygenation status and to evaluate their role as potential surrogate biomarkers of 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) dynamic susceptibility contrast (DSC)-MRI measures of red blood cell (RBC) flow and distribution will better delineate regions of abnormal vessel physiology as compared to plasma hemodynamic parameters, and iii) a multi-parameter MRI assessment of the tumor microenvironment can differentiate between normoxic and hypoxic tissue. 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 the effects of oxygen modulation. We will evaluate and incorporate corrections for the influence of local tissue pH and hematocrit on these measurements and assess the usefulness of this method to track changes with therapy (Aim 1). The proposed DSC-MRI studies will develop protocols and contrast agents to evaluate red blood cell (RBC) flow, volume, and mean transit time in tumors and compare and contrast these measures to those derived from plasma-distributed contrast agents (Aim 2). The BOLD and DSC-MRI parameters will then be integrated with other physiological measures derived from diffusion-weighted (DW) MRI and PET/CT to provide a quantitative assessment of the underlying mechanisms driving the development of tumor hypoxia (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 antiangiogenic and/or oxygen-enhancing treatments.