Quantitative MRI Assessment of Tumor Hypoxia and Angiogenesis

描述（由申请人提供）：人们普遍认为缺氧和血管生成是控制肿瘤侵袭性的重要因素。这些特征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，特别是考虑到血管生成抑制剂和氧增强剂的临床应用的最新进展。因此，本申请的长期目标是开发用于表征肿瘤血管形态、功能和氧合状态的定量MRI方法，并评价其作为缺氧和治疗反应的潜在替代生物标志物的作用。该建议的一般假设是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）与血浆血液动力学参数相比，红细胞（RBC）流动和分布的动态磁化率对比（DSC）-MRI测量将更好地描绘异常血管生理学的区域，和iii）肿瘤微环境的多参数MRI评估可以区分常氧和缺氧组织。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的影响。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结果的影响的校正，并评估该方法在跟踪治疗变化方面的有用性（目的1）。拟议的DSC-MRI研究将开发方案和造影剂，以评价肿瘤中的红细胞（RBC）流量、体积和平均通过时间，并将这些指标与血浆分布造影剂的指标进行比较和对比（目标2）。然后，将BOLD和DSC-MRI参数与来自扩散加权（DW）MRI和PET/CT的其他生理测量值整合，以提供驱动肿瘤缺氧发展的潜在机制的定量评估（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。

DESCRIPTION (provided by applicant): 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 anti-angiogenic and/or oxygen-enhancing treatments.