MRI Assessment of Glucose Metabolism in Brain Tumor Using GlucoCEST

描述（由申请人提供）：为了改善恶性脑肿瘤的预后，非常需要分子和代谢成像方法来揭示葡萄糖代谢和肿瘤生理学。特别是，高度侵袭性的胶质母细胞瘤由于扩散的边界和侵入周围组织而具有不良预后。FDG-PET是肿瘤葡萄糖摄取代谢成像的成功范例;不幸的是，其脑肿瘤对比度受到与脑中高葡萄糖代谢的竞争的限制。最近，分子靶向治疗，如葡萄糖剥夺，已显示出改善许多侵袭性肿瘤，包括胶质母细胞瘤的治疗指数的希望。因此，需要开发成像方法来监测成胶质细胞瘤治疗后的葡萄糖利用和分子改变。我们和其他人最近开发了葡萄糖的化学交换饱和转移（CEST）MR成像（glucoCEST）作为检测葡萄糖摄取的分子方法。它允许直接和灵敏地检测D-葡萄糖上的羟基质子，D-葡萄糖是一种天然的非放射性底物。此外，它是一种显示分子对比度的水成像方法，允许对毫摩尔浓度的试剂进行良好的分辨率图像。 我们提出的研究的长期目标是利用glucoCEST方法并将其转化为临床脑肿瘤分期和分级，以及评估肿瘤对治疗的反应。作为该原理的初步演示，我们的目标是开发一个全面的glucoCEST对比模型，专注于肿瘤中葡萄糖代谢和酸中毒的成像，并使用这些发现来监测治疗。核心假设是glucoCEST直接检测D-葡萄糖，从而能够监测其摄取。此外，glucoCEST造影剂对肿瘤微环境中pH值的变化敏感。如我们的第一项研究和初步数据所示，酸性pH下的glucoCEST对比曲线不同于 在生理pH下，证明了在肿瘤血管外细胞外间隙（EES）中成像酸中毒的潜力。我们的假设将通过两个具体的目的进行验证：1）在胶质母细胞瘤动物模型中检查glucoCEST的来源并了解其机制; 2）将glucoCEST技术应用于监测脑肿瘤的葡萄糖剥夺治疗。在目标1中，我们将确定原位植入的人胶质母细胞瘤动物模型中血管空间、EES和细胞内空间对glucoCEST对比度的贡献。我们还将通过与动态灌注MRI和13 C NMR进行比较，验证测量葡萄糖累积和洗脱动力学的能力。在目的2中，我们将应用目的1中建立的glucoCEST模型来评估糖剥夺对荷胶质母细胞瘤小鼠的治疗效果。这些目标预计将显示glucoCEST的相关性，以研究葡萄糖动力学和监测治疗脑肿瘤反复和非侵入性。该研究的创新之处在于直接检测天然D-葡萄糖而无需额外标记，并同时评估肿瘤EES中的葡萄糖利用和酸中毒。最终，这种成像平台有可能改变目前的肿瘤生理学成像模式，并提供一种非侵入性的方式来成像肿瘤中的葡萄糖代谢。此外，这可能为其他疾病（如缺血性中风）的成像开辟新的途径。

DESCRIPTION (provided by applicant): To improve the prognosis of malignant brain tumors, it is highly desirable to have a molecular and metabolic imaging approach to reveal both the glucose metabolism and tumor physiology. In particular, highly aggressive glioblastoma has a poor prognosis due to a diffused boundary and the invasion into the surrounding tissues. FDG-PET has been a successful example of metabolic imaging of glucose uptake in tumors; unfortunately, its brain tumor contrast is limited by competition with the high glucose metabolism in the brain. Recently, molecular-targeted therapies, such as glucose deprivation, have shown promise in improving the therapeutic index of many aggressive tumors including glioblastoma. Thus, there is a need to develop imaging approaches for monitoring glucose utilization and molecular alterations in glioblastomas upon treatments. We and others recently developed Chemical Exchange Saturation Transfer (CEST) MR imaging of glucose (glucoCEST) as a molecular approach to detect glucose uptake. It allows a direct and sensitive detection of hydroxyl protons on D-glucose, a natural non-radioactive substrate. Moreover, it is a water imaging approach showing molecular contrast, allowing good resolution images for agents in millimolar concentrations. The long-term goal of our proposed study is to exploit the glucoCEST approach and translate it to the clinic for brain tumor staging and grading, as well as assessing tumor responses to therapies. As an initial demonstration of the principle, we aim to develop a comprehensive model for glucoCEST contrast, focus on the imaging of glucose metabolism and acidosis in tumors, and use these findings to monitor treatments. The central hypothesis is that glucoCEST detects D-glucose directly, thus enabling the monitoring of its uptake. In addition, glucoCEST contrast is sensitive to changes in pH in the tumor microenvironment. As shown in our first study and preliminary data, the glucoCEST contrast profile at acidic pH is different from that at physiological pH, demonstrating the potential to image acidosis in the extravascular extracellular space (EES) of tumors. Our hypothesis will be tested through two specific aims: 1) To examine the origin and understand the mechanism of glucoCEST in glioblastoma animal model; 2) To apply the glucoCEST technology to monitor glucose deprivation treatment of brain tumors. In Aim 1, we will identify the contributions to glucoCEST contrast from the vascular space, EES and intracellular space in an orthotopically implanted human glioblastoma animal model. We will also validate the ability to measure kinetics of glucose buildup and washout through comparison with dynamic perfusion MRI and 13C NMR. In Aim 2, we will apply the established glucoCEST model in Aim 1 to evaluate the therapeutic outcomes of glucose deprivation in mice bearing glioblastoma. These aims are expected to show the relevance of glucoCEST to study glucose kinetics and monitoring therapy in brain tumors repeatedly and non-invasively. The innovation of the proposed study is the direct detection of natural D-glucose without additional labeling, and the assessment of glucose utilization and acidosis in the EES of tumors simultaneously. Ultimately, this imaging platform has the potential to shift the current paradigm of imaging tumor physiology, and provide a non-invasive way to image glucose metabolism in tumors. Moreover, this could open up new avenue for imaging of other diseases, such as ischemic stroke.