Validation of imaging brain tumor metabolism using deuterated glucose

使用氘化葡萄糖验证脑肿瘤代谢成像

• 批准号: 10560260
• 负责人: ROBIN A DE GRAAF
• 金额: $ 49.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560260
• 关键词: 3-Dimensional; Achievement; Address; Benchmarking; Brain; Brain Neoplasms; Brain imaging; Cells; Choline; Clinic; Clinical; Consumption; Coupling; Deoxyglucose; Detection; Deuterium; Development; Diagnosis; Disease; Disease Management; Disease Progression; Dose; Early Diagnosis; Evaluation; Evolution; Foundations; Future; Glioblastoma; Glucose; Glutamates; Glutamine; Glycolysis; Goals; Image; Imaging Device; Imaging Techniques; Immune; Infusion procedures; Label; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Measurement; Measures; Metabolic; Metabolism; Methods; Monitor; N-acetylaspartate; Normal tissue morphology; Oxygen; Pathway interactions; Patients; Pattern; Performance; Positron-Emission Tomography; Primary Brain Neoplasms; Process; Radioactive; Research; Research Project Grants; Rodent Model; Scanning; Signal Transduction; Solid Neoplasm; Staging; Techniques; Technology; Testing; Time; Tissues; Tumor Volume; Validation; Visualization; Warburg Effect; analog; brain tumor imaging; cancer cell; chemotherapy; contrast imaging; early detection biomarkers; glucose metabolism; glucose uptake; imaging modality; improved; in vivo; insight; magnetic resonance spectroscopic imaging; metabolic imaging; neuro-oncology; new technology; oxidation; response biomarker; standard of care; technique development; temozolomide; tool; treatment effect; treatment response; tumor; tumor growth; tumor metabolism; tumor progression

Aberrant metabolism is increasingly recognized as a hallmark of cancer. The Warburg effect is a well-known example of such abnormal cancer metabolism, which entails a shift away from oxidative to glycolytic glucose metabolism (despite the presence of oxygen) and usually also increased glucose uptake. The detection of this increased glucose uptake, via a radioactive analogue (2-18F-fluoro-2-deoxy-D-glucose, FDG) with positron emission tomography (PET), is often used for diagnosis, staging, and evaluating disease progression of tumors outside the brain. However, in patients with brain tumors FDG-PET is frequently inconclusive because the normal high glucose uptake in healthy brain is comparable to that in tumors, thereby obscuring the tumor-to-brain image contrast. As a result, FDG-PET is not frequently used in these patients. That leaves brain tumor patients without the benefits of metabolic imaging, which has a significant negative impact on the management of their disease. The recently developed MRI-based method, deuterium metabolic imaging (DMI) can be an alternative strategy to detect abnormal glucose metabolism. DMI is based on 3D deuterium (2H) magnetic resonance spectroscopic imaging (MRSI). After administration of the nonradioactive deuterated glucose, DMI can detect both glucose and its downstream metabolites lactate and glutamate. In cancer cells that show the Warburg effect the 2H-labeling in lactate and glutamate reflects the typical shift from oxidative to glycolytic metabolism. DMI can detect this 2H-labeling and reveal the cancer-specific glucose metabolism with high tumor-to-brain image contrast. Because of these features and the ease of use of the method, DMI can become a robust metabolic imaging technique for brain tumors that so far has been missing. The goal of this proposal is to validate DMI of glucose metabolism as a potential imaging tool for neurooncology, particularly for glioblastoma, the most common and lethal primary brain tumor. We envision that, for patients with brain tumors, DMI can provide a similar benefit as FDG-PET has for many patients with tumors outside of the brain. In Aim 1 we therefore seek to validate the 2H-labeling pattern in lactate and glutamate detected with DMI as surrogates of the Warburg effect, by comparing them with absolute measurements of the Warburg effect in rodent models of GBM. Aim 2 is focused on the potential of DMI to provide an early biomarker of response to standard of care chemotherapy. To confirm the improved performance of DMI relative to current clinically available methods, in Aim 3 metabolic maps generated by 1H MRSI, FDG-PET and DMI, are compared for tumor-to-brain image contrast in patients with GBM. The proposed aims will provide better understanding of the fundamental processes underlying the DMI-based image contrast, provide the first insight in its value for monitoring therapy and disease progression, and benchmark its performance as a new metabolic imaging method. These achievements will strengthen the foundation for further development of DMI as a clinically viable technology for metabolic imaging.

异常代谢越来越被认为是癌症的标志。 Warburg效应是众所周知的 这种异常癌症代谢的例子，它需要从氧化型糖酵解葡萄糖转变 代谢（尽管存在氧气），并且通常也增加了葡萄糖摄取。检测 通过放射性类似物（2-18F-氟-2-脱氧-D-葡萄糖，FDG）增加了葡萄糖摄取 发射断层扫描（PET）通常用于诊断，分期和评估肿瘤疾病进展 在大脑外。但是，在患有脑肿瘤的患者中，FDG-PET经常尚无定论，因为正常 健康大脑中的高葡萄糖吸收与肿瘤中的葡萄糖吸收相当，从而掩盖了肿瘤至脑的图像 对比。结果，这些患者不经常使用FDG-PET。使脑肿瘤患者没有 代谢成像的好处，这对疾病的管理产生了重大负面影响。 最近开发的基于MRI的方法，氘代谢成像（DMI）可以是一种替代方法 检测异常葡萄糖代谢的策略。 DMI基于3D氘（2H）磁共振 光谱成像（MRSI）。给予非放射性脱位的葡萄糖后，DMI可以检测到 葡萄糖及其下游代谢产物乳酸和谷氨酸。在显示沃堡效应的癌细胞中 乳酸和谷氨酸中的2H标记反映了从氧化剂到糖酵解代谢的典型转移。 DMI可以 检测此2H标记并揭示具有高肿瘤至脑图像的癌症特异性葡萄糖代谢 对比。由于这些功能和该方法的易用性，DMI可以成为强大的代谢 到目前为止缺少脑肿瘤的成像技术。 该建议的目的是验证葡萄糖代谢的DMI作为潜在的成像工具 神经学，特别是针对胶质母细胞瘤，是最常见和致命的原发性脑肿瘤。我们设想， 对于患有脑肿瘤的患者，DMI可以像FDG-PET一样提供类似的好处 在大脑外。因此，在AIM 1中，我们试图验证乳酸和谷氨酸中的2H标记模式 通过将其与绝对测量值进行比较，用DMI作为Warburg效应的替代物检测到 Warburg的啮齿动物模型的效应。 AIM 2专注于DMI提供早期生物标志物的潜力 对护理化疗的反应。确认DMI相对于电流的性能提高 比较了AIM 3 MRSI，FDG-PET和DMI产生的AIM 3代谢图 对于GBM患者的肿瘤对比对比度。拟议的目标将提供更好的理解 基于DMI的图像对比的基本过程，为其价值提供了第一个见解 监测疗法和疾病进展，并将其作为新的代谢成像的表现基准 方法。这些成就将增强DMI作为临床可行的进一步发展的基础 代谢成像的技术。