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.

代谢异常越来越被认为是癌症的标志。瓦尔堡效应是众所周知的 这种异常癌症代谢的例子，它需要从氧化葡萄糖转变为糖酵解葡萄糖 新陈代谢（尽管存在氧气）并且通常也会增加葡萄糖的摄取。对此的检测 通过带有正电子的放射性类似物（2-18F-氟-2-脱氧-D-葡萄糖，FDG）增加葡萄糖摄取 发射断层扫描 (PET) 通常用于肿瘤的诊断、分期和评估疾病进展 大脑之外。然而，对于脑肿瘤患者，FDG-PET 通常无法得出结论，因为正常的 健康大脑中的高葡萄糖摄取量与肿瘤中的高葡萄糖摄取量相当，从而模糊了肿瘤到大脑的图像 对比。因此，FDG-PET 不常用于这些患者。这使得脑肿瘤患者无法 代谢成像的好处，这对其疾病的管理有显着的负面影响。 最近开发的基于 MRI 的方法，氘代谢成像 (DMI) 可以作为替代方法 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）。给予非放射性氘代葡萄糖后，DMI 可以检测到 葡萄糖及其下游代谢物乳酸和谷氨酸。在表现出瓦尔堡效应的癌细胞中 乳酸和谷氨酸中的 2H 标记反映了从氧化代谢到糖酵解代谢的典型转变。 DMI 可以 检测这种 2H 标记并通过高肿瘤到大脑图像揭示癌症特异性葡萄糖代谢 对比。由于这些特征和该方法的易用性，DMI 可以成为一种强大的代谢方法 迄今为止一直缺失的脑肿瘤成像技术。 该提案的目标是验证葡萄糖代谢的 DMI 作为潜在的成像工具 神经肿瘤学，特别是胶质母细胞瘤，这是最常见和致命的原发性脑肿瘤。我们设想， 对于脑肿瘤患者，DMI 可以为许多肿瘤患者提供与 FDG-PET 类似的益处 大脑之外。因此，在目标 1 中，我们寻求验证乳酸和谷氨酸中的 2H 标记模式 通过将 DMI 与 Warburg 效应的替代品进行比较，将它们与绝对测量值进行比较来检测 GBM 啮齿动物模型中的 Warburg 效应。目标 2 重点关注 DMI 提供早期生物标志物的潜力 对标准护理化疗的反应。确认 DMI 相对于当前的性能改进 Aim 3 中对 1H MRSI、FDG-PET 和 DMI 生成的代谢图谱中的临床可用方法进行了比较 用于 GBM 患者的肿瘤与大脑图像对比。拟议的目标将有助于更好地理解 基于 DMI 的图像对比度的基本过程，提供了对其价值的初步见解 监测治疗和疾病进展，并将其性能作为新的代谢成像的基准 方法。这些成就将为 DMI 进一步发展为临床可行的药物奠定基础。 代谢成像技术。