Mapping of choline uptake and metabolism in brain tumors with deuterium metabolic imaging (DMI)

利用氘代谢成像 (DMI) 绘制脑肿瘤中胆碱的摄取和代谢图

• 批准号: 10575169
• 负责人: Henk De Feyter
• 金额: $ 8.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-05 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575169
• 关键词: 3-Dimensional; Anatomy; Animal Model; Animals; Brain; Brain Diseases; Brain Mapping; Brain Neoplasms; Brain imaging; Cell Proliferation; Cell membrane; Cells; Choline; Clinic; Clinical; Clinical Research; Data; Deoxyglucose; Detection; Deuterium; Development; Disease Management; Disease Progression; Dose; Evaluation; Future; Glioblastoma; Glioma; Goals; Growth; Human; Hydrogen; Imaging Device; Imaging Techniques; Label; Lesion; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Measures; Medical Imaging; Metabolic; Metabolism; Methods; Modeling; Mus; Normal tissue morphology; Nutrient; Oligodendroglioma-Astrocytoma; Patients; Phospholipids; Positioning Attribute; Positron-Emission Tomography; Primary Brain Neoplasms; Prognosis; Proliferating; Radioactive; Research Project Grants; Resolution; Rodent Model; Scanning; Signal Transduction; Solid; Specificity; Techniques; Testing; Therapeutic; Tissues; Tracer; Translating; Translations; Tumor Tissue; Tumor Volume; brain size; brain tissue; brain tumor imaging; cancer type; chemotherapeutic agent; clinical translation; contrast imaging; detection sensitivity; dietary supplements; early detection biomarkers; experimental study; glucose analog; glucose metabolism; glucose uptake; imaging detection; imaging modality; imaging probe; improved; in vivo; insight; magnetic resonance spectroscopic imaging; membrane synthesis; metabolic abnormality assessment; metabolic imaging; mouse model; novel; response; stable isotope; standard of care; temozolomide; treatment effect; treatment response; tumor; tumor growth; tumor metabolism; tumor specificity; uptake

PROJECT SUMMARY While neuro-oncologists rely heavily on medical imaging, particularly magnetic resonance imaging (MRI) for detection and sizing of brain tumors, they do not have access to a robust method that shows the active metabolism of tumor lesions. Positron emission tomography (PET) detection of the radioactive glucose analog 18F-deoxyglucose (FDG) is widely used for metabolic imaging of many solid cancers outside of the brain. FDG- PET detects high glucose uptake, which is often a sign of active and growing tissue, such as in proliferating tumors. However, when used for scanning tumors in the brain FDG-PET has shown to be often inconclusive. This is not due to any technical limitation, but merely the consequence of the high glucose uptake of normal brain, leading to high background signal and thus low metabolic image contrast between brain and tumor. Choline is an essential nutrient, and proliferating cells need choline for phospholipid and membrane synthesis. As a result, many types of cancer have evolved with a high capacity for choline uptake and metabolism. In contrast, choline uptake in normal brain is in comparison very low. Our preliminary data indicate that the detection of deuterated choline uptake and metabolism using the novel technique Deuterium Metabolic Imaging (DMI) can provide high brain tumor-specific image contrast with surrounding brain. DMI of deuterium (2H)-labeled choline allows detection of choline uptake and/or choline metabolism, simply by varying the timing of the scan in relation to the start of the choline administration. These features make choline DMI a very promising metabolic imaging technique for use in brain tumors. The overall objective is to investigate the potential of choline DMI as a metabolic imaging method for brain cancer. In this R03 research project we propose to investigate the value of mapping choline uptake and metabolism with DMI as correlate for brain tumor grade and prognosis (Aim 1), and evaluating treatment effect (Aim 2). We will use two established mouse models of brain tumor grade 3, and grade 4 glioma, and test the effect of temozolomide, the standard of care chemotherapeutic, on tumor choline uptake and metabolism. Choline is an essential nutrient and used as a nutritional supplement within and outside of clinical settings, at very high but safe doses. Deuterium is a stable isotope and commonly used as a tracer for metabolic studies. Finally, DMI is a highly translatable imaging technique, already applied in clinical research settings. Therefore, if the potential of mapping of choline uptake and metabolism is established in these rodent models, rapid translation of DMI for detection of deuterium-labeled choline in human patients is relatively straightforward.

项目摘要 尽管神经肿瘤学家在很大程度上依赖医学成像，但尤其是磁共振成像（MRI） 检测和大小的脑肿瘤，它们无法获得显示活性的强大方法 肿瘤病变的代谢。放射性葡萄糖类似物的正电子发射断层扫描（PET）检测 18F-脱氧葡萄糖（FDG）广泛用于大脑外许多固体癌症的代谢成像。 FDG- PET检测到高葡萄糖的吸收，这通常是活性和生长组织的迹象，例如增殖 肿瘤。但是，当用于扫描脑部肿瘤时，FDG-PET通常显示出尚无定论。 这不是由于任何技术限制，而只是正常葡萄糖吸收的结果 大脑，导致较高的背景信号，因此大脑和肿瘤之间的代谢形象对比度低。 胆碱是必不可少的营养素，增殖细胞需要胆碱作为磷脂和膜 合成。结果，许多类型的癌症随着胆碱摄取的高能力而进化 代谢。相反，相比之下，正常大脑中的胆碱摄取非常低。我们的初步数据表示 使用新型技术代谢，检测氘化的胆碱摄取和代谢 成像（DMI）可以提供与周围大脑的高脑肿瘤特异性图像对比。氘的DMI （2H）标签胆碱允许检测胆碱摄取和/或胆碱代谢，仅通过改变时间来检测 与胆碱给药开始有关的扫描。这些功能使胆碱DMI变得非常有前途 用于脑肿瘤的代谢成像技术。 总体目的是研究胆碱DMI作为大脑的代谢成像方法的潜力 癌症。在此R03研究项目中，我们建议调查映射胆碱摄取和 DMI的代谢与脑肿瘤等级和预后相关（AIM 1），并评估治疗效果 （目标2）。我们将使用两种已建立的脑肿瘤3级小鼠模型和4级神经胶质瘤，并测试 Temozolomide（护理化学治疗标准）对肿瘤胆碱摄取和代谢的影响。 胆碱是必不可少的营养素，用作临床环境内外的营养补充剂， 以很高但安全的剂量。氘是一种稳定的同位素，通常用作代谢研究的示踪剂。 最后，DMI是一种已应用于临床研究环境中的高度可翻译成像技术。因此，如果 在这些啮齿动物模型中建立了胆碱摄取和代谢的映射的潜力，快速 在人类患者中检测DMI用于检测氘标记的胆碱的翻译相对简单。