MRI Biomarkers of Response in Cerebral Tumors

描述(申请人提供)：恶性胶质瘤在治疗上有很大的困难，在过去的25年中，12个月的中位生存期几乎没有变化。目前的治疗方案包括手术、放射治疗(RT)和化疗。旨在抑制新血管形成(抗血管生成治疗)或摧毁已形成的肿瘤血管(血管干扰剂)的新疗法显示出希望。这项应用将使用磁共振(MR)造影剂(CAS)和MR检测来测量脑肿瘤的血容量、血到脑的跨血管传输常数、血管外细胞外空间和总细胞外空间，并使用MR动脉自旋标记来测量肿瘤的血流量。这些参数是对正常和肿瘤血管系统生理学的重要总结。建议将这些血管参数作为脑胶质瘤动物模型的MR生物标记物。在一系列实验中，我们将检查在抗血管生成治疗、血管阻断剂和放疗后MR测量的血管参数的变化，所有MR测量与模型肿瘤中血管和细胞密度的组织病理学评估相关。在研究了单药疗法后，将研究联合疗法，并通过组织病理学评估和长期生存来判断MRI血管生物标记物作为疗效的预测因子。在这些研究完成后，将建立MR测量的血管参数与细胞对单一和联合治疗的反应的关系，并评估MR测量的血管参数作为长期生存预测因子的有效性。磁共振测量的参数可以转化为临床使用，并作为人类肿瘤对治疗反应的预测因子进行评估。这些研究代表了癌症治疗提供方式从启发式和公式化方法向图像引导治疗和反应监测的个性化计划转变的第一步。 公共卫生相关性：将展示定量MR测量的血管参数用于预测脑瘤对有前景的抗血管生成剂和血管干扰剂单独应用或与放射治疗联合应用的反应。目前的研究代表了癌症治疗交付的范式转变的第一步，从一刀切的方法到图像引导的治疗和反应监测的个性化计划。

DESCRIPTION (provided by applicant): Malignant gliomas present great difficulties in treatment, with little change over the past 25 years in the median survival time of 12 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments), or destroying formed tumor vasculature (vascular disrupting agents) show promise. This application will use magnetic resonance (MR) contrast agents (CAs) and MR detection to measure blood volume, the blood-to-brain transvascular transfer constant, the extravascular extracellular space, and the total extracellular space in cerebral tumors, and also to measure tumor blood flow using MR arterial spin tagging. These parameters present an important summary of the physiology of vasculature, both normal and tumorous. It is proposed to use these vascular parameters as MR biomarkers in animal models of cerebral gliomas. In a series of experiments, we will examine the change in MR-measured vascular parameters after antiangiogenic therapy, after vascular disrupting agent, and after RT, with all MR measures correlated with histopathological assessments of vascular and cellular density in the model tumors. After single-agent therapies are studied, combination therapies will be studied, and MRI vascular biomarkers will be examined as predictors of response as judged both by histopathological assessments and long-term survival. At the completion of these studies, the relation of MR-measured vascular parameters to cellular responses to single and combination therapies will be established, and the utility of MR-measured vascular parameters as predictors of long-term survival assessed. The MR-measured parameters can be translated to clinical use and evaluated as predictors of human tumor response to therapies. These studies represent a first step in a paradigm shift in cancer treatment delivery from a heuristic and formulaic approach to an individualized plan of image guided treatment and response monitoring. PUBLIC HEALTH RELEVANCE: The utility of quantitative MR-measured vascular parameters for predicting brain tumor response to promising anti-angiogenic agents and vascular disrupting agents applied singly or in combination with or without radiation therapy will be shown. The studies presented represent a first step in a paradigm shift in cancer treatment delivery from a one-solution-fits-all approach to an individualized plan of image guided treatment and response monitoring.