Quantitative MRI Assessment of Tumor Hypoxia and Angiogenesis

缺氧和血管生成是控制肿瘤侵袭性的重要因素， 肿瘤的这些特征的非侵入性定量成像可以改善临床管理， 治疗癌症患者，特别是考虑到最近的进展，在临床应用中， 血管生成抑制剂和氧增强剂。因此，本申请的长期目标是 开发定量MRI方法，用于表征肿瘤血管形态、功能和 氧合状态，并评估其作为缺氧和治疗的潜在替代生物标志物的作用 反应该提议的一般假设是i）结合对比度效应的联合收割机的MRI方法 具有血氧水平依赖性（BOLD）测量的试剂可以可靠地用于监测肿瘤 氧变化，ii）红细胞（RBC）流动的动态磁化率对比（DSC）-MRI测量，以及 与血浆血流动力学相比，分布将更好地描绘异常血管生理学区域 参数，和iii）肿瘤微环境的多参数MRI评估可以区分 正常和缺氧组织之间的区别拟议的研究侧重于开发和验证一个 具有分离和量化肿瘤血管反应性潜力的对比增强BOLD方法 以及氧气调节的效果。我们将评估和纳入当地的影响校正 组织pH值和红细胞压积对这些测量值的影响，并评估这种方法对跟踪 随着治疗的变化（目标1）。拟议的DSC-MRI研究将制定方案和造影剂， 评估肿瘤中的红细胞（RBC）流量、体积和平均通过时间，并比较和对比这些指标 测量来自血浆分布的造影剂（目标2）。BOLD和DSC-MRI 然后将参数与从扩散加权（DW）导出的其他生理测量值进行整合 MRI和PET/CT，以提供对驱动 肿瘤缺氧的发展（目的3）。意义：一旦开发和验证这些新方法， 为改善临床管理和测量新的抗血管生成药物的疗效提供定量工具 和/或氧增强处理。

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.