Quantitative MRI Assessment of Tumor Vascular and Oxygen Reactivity

描述(申请人提供)：人们普遍认为低氧是控制肿瘤侵袭性的重要因素，低氧组织对传统疗法更具抵抗力。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气增强剂的临床测试。因此，这一应用的长期目标是发展定量的MRI方法来表征肿瘤的氧合状态，并评估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。这一建议的一般假设是：i)将造影剂的效果与血氧水平依赖(BOLD)测量相结合的MRI方法可以可靠地用于监测肿瘤的氧气变化；ii)在最大氧饱和度扰动后对血容量、血管反应性和氧调制的评估可以用于区分常氧和低氧组织；iii)增强的BOLD MRI可以用于改进抗血管生成药物和放射治疗的治疗计划。这些研究提出的重点是开发和验证对比剂增强的BOLD方法，该方法具有分离和量化肿瘤血管反应性和氧气调节的潜力。我们将评估并纳入局部组织pH和红细胞压积对这些测量的影响的校正(目标1)。增强后的BOLD参数和肿瘤缺氧的验证将通过与组织学和PET试剂[18F]氟异硝唑(FMISO)摄取的比较来实现(目标2)。最后，BOLD参数将应用于小鼠癌症模型，以计划和监测抗血管生成剂、增氧剂和放射治疗的反应(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。人们普遍认为，低氧或低氧会增加肿瘤的侵袭性，降低传统疗法的有效性。能够识别具有缺氧区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，特别是考虑到最近设计的改善肿瘤氧合的药物的临床测试。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针对缺氧肿瘤的有前景的新药物来证明其临床意义。

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.