Quantitative MRI Assessment of Tumor Hypoxia and Angiogenesis

描述(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能会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气增强剂的临床应用的最新进展。因此，这一应用的长期目标是发展定量的MRI方法来表征肿瘤血管的形态、功能和氧合状态，并评估它们作为潜在的缺氧和治疗反应的替代生物标志物的作用。这一建议的一般假设是：i)结合造影剂效果和血氧水平依赖(BOLD)测量的MRI方法可以可靠地用于监测肿瘤的氧气变化，ii)动态磁化率对比(DSC)-与血浆血流动力学参数相比，红细胞(RBC)流动和分布的MRI测量将更好地描绘异常血管生理区域，以及iii)对肿瘤微环境的多参数MRI评估可以区分正常和缺氧组织。这些研究提出的重点是开发和验证对比剂增强的BOLD方法，该方法有可能分离和量化肿瘤血管的反应性和氧气调节的影响。我们将评估和纳入局部组织pH和红细胞压积对这些测量的影响的校正，并评估该方法在跟踪治疗变化方面的有效性(目标1)。拟议的DSC-MRI研究将开发方案和造影剂，以评估红细胞(RBC)在肿瘤中的流动、体积和平均通过时间，并将这些测量方法与血浆分布造影剂的测量方法进行比较和对比(目标2)。BOLD和DSC-MRI参数随后将与来自扩散加权(DW)MRI和PET/CT的其他生理测量相结合，以提供对推动肿瘤缺氧发展的潜在机制的定量评估(目标3)。意义：一旦开发和验证，这些新方法将为改善临床管理和测量新的抗血管生成和/或增氧治疗的有效性提供量化工具。

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.