Development of Quantitative Deuterium MRS Imaging for Human Brain Tumor Application at Ultrahigh Field

超高场定量氘 MRS 成像在人脑肿瘤应用中的发展

基本信息

批准号：
10207550
负责人：
Clark Chin-Chung Chen
金额：
$ 17.96万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10207550
关键词：
3-Dimensional Adult Animal Experimentation Animals Area Basic Science Biochemical Biological Biopsy Specimen Brain Brain Neoplasms Caring Cell Respiration Cells Cerebrum Chemotherapy and/or radiation Citric Acid Cycle Clinic Clinical Clinical Treatment Computer software Data Detection Deuterium Development Diagnosis Disease Energy Metabolism Engineering Fatality rate Functional disorder Funding Future Glioblastoma Glucose Glutamates Glutamine Glycolysis Goals Human Human body Ice Image Imaging Techniques Imaging technology Immune Intake Interdisciplinary Study Intravenous infusion procedures Label Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant Neoplasms Malignant neoplasm of brain Measurement Measures Metabolic Metabolic Marker Methods Minnesota Mitochondria Modality Modeling Monitor Mutation Neurosurgeon Noise Normal tissue morphology Operative Surgical Procedures Oral Outcome Pathologic Pathology Patients Physiologic pulse Pilot Projects Positron-Emission Tomography Production Prognosis Property Pyruvate RF coil Radiation therapy Research Research Personnel Resistance Resolution Sensitivity and Specificity Signal Transduction Site Specificity Specimen Techniques Technology Testing Time Training United States National Institutes of Health Universities Warburg Effect Work aerobic glycolysis anticancer research base brain disorder diagnosis brain morphology brain tissue cancer cell clinical Diagnosis contrast imaging cost effective data analysis pipeline expectation fluorodeoxyglucose glucose metabolism glucose uptake human imaging image processing imaging modality imaging study improved in vivo indexing innovation kinetic model magnetic field magnetic resonance spectroscopic imaging metabolic imaging metabolic rate neuro-oncology neurochemistry neuroimaging neuropathology novel novel imaging technique novel therapeutics oxidation quantitative imaging software development spatiotemporal spectroscopic imaging success therapeutic development tool treatment response tumor tumor heterogeneity tumor progression

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is the most aggressive form of human cancers with very high fatality rate and short survival time, and the cancer cells aggressively infiltrate the brain and are intrinsically resistant to chemotherapy and radiation therapy. Intra-tumoral heterogeneity is a major challenge in therapeutic development for GBM patients because surgical acquisition of clinical specimens cannot be used to monitor the tumor progression and/or the underlying metabolic changes. Various neuroimaging methods have been used to study the morphology of the brain tumors. However, the need for noninvasively characterizing the brain tumors and their metabolic features has not been met, which should be critical for prognosis or for monitoring the tumor progression and response to treatment. It is well known that a common hallmark of the cancer cells is disrupted glucose metabolism, in which upregulated glycolysis is accompanied by inhibited mitochondrial oxidation, i.e., the “Warburg effect”. Imaging the “Warburg effect” and its spatial variability in brain tumors is a new attempt that can have a major impact on cancer research, particularly in the treatment of GBM, because therapies aimed at reversing the Warburg effect have shown promise in GBM ; however, great efforts are needed to develop novel metabolic imaging techniques to achieve the capabilities sought by clinicians. We have recently initiated a project aiming to develop a neuroimaging technique based on deuterium (2H) MRS (DMRS) detection of 2H-labeled brain metabolites following an administration of D-Glucose-6,6-d2 (d66). Our preliminary results indicate that the dynamic DMRS imaging can determine the cerebral metabolic rates of glucose (CMRGlc) and TCA cycle (VTCA), thus, the lactate production rate (CMRLac) in addition to the concentrations of deuterium-labeled glucose (Glc), mixed glutamate/glutamine (Glx) and lactate (Lac) in living brains. Furthermore, we demonstrated for the first time that the uncoupling between the glycolysis and oxidation in brain tumor can be quantitatively imaged via mapping the [Lac]/[Glx] ratio defined as an index of Warburg effect (IWE); and it has been shown that IWE is highly sensitive for distinguishing brain tumor from surrounding normal tissues. In this application, we are seeking NIH funding support to move forward with the DMRS imaging development through: i) integrated hardware and software development and the ultrahigh field MR technology to further boost signal-to-noise ratio (SNR), spectral resolution and spatiotemporal resolution; ii) testing the ultrahigh resolution DMRS imaging in healthy subject, and tumor patients and establishing a quantification model and imaging processing pipeline for future application; and iii) comparing the DMRS imaging results with the neuropathological and immunohistochemical findings of the biospecimens to understand the correlation between the DMRSI measurements and biological features of brain tumor. Our interdisciplinary research team with unique expertise is ready for a full-scale development of this highly innovative and cost-effective neuroimaging essential for basic research and clinic application in neuro-oncology.

项目概要胶质母细胞瘤 (GBM) 是人类癌症中最具侵袭性的一种，死亡率非常高，且发病时间短。生存时间，癌细胞积极浸润大脑并具有内在抵抗力化疗和放疗的肿瘤内异质性是治疗的主要挑战。 GBM 患者的发展，因为手术采集的临床标本不能用于监测肿瘤进展和/或潜在的代谢变化已经有多种神经影像学方法。用于研究脑肿瘤的形态然而，需要非侵入性地表征大脑。肿瘤及其代谢特征尚未得到满足，这对于预后或监测至关重要众所周知，肿瘤的进展和对治疗的反应是癌细胞的共同特征。葡萄糖代谢被破坏，其中糖酵解上调伴随着线粒体受抑制氧化，即“瓦尔堡效应”，成像“瓦尔堡效应”及其在脑肿瘤中的空间变异性。可能对癌症研究，特别是 GBM 治疗产生重大影响的新尝试，因为旨在逆转 Warburg 效应的疗法已在 GBM 中显示出希望，但仍需付出巨大努力；需要开发新颖的代谢成像技术来实现上级所寻求的能力。我们最近启动了一个项目，旨在开发基于氘 (2H) 的神经成像技术施用 D-Glucose-6,6-d2 (d66) 后进行 2H 标记脑代谢物的 MRS (DMRS) 检测。我们的初步结果表明，动态 DMRS 成像可以确定大脑代谢率葡萄糖 (CMRGlc) 和 TCA 循环 (VTCA)，因此，除了活体中氘标记的葡萄糖 (Glc)、混合谷氨酸/谷氨酰胺 (Glx) 和乳酸 (Lac) 的浓度此外，我们首次证明了糖酵解和大脑之间的解偶联。脑肿瘤中的氧化可以通过绘制 [Lac]/[Glx] 比率（定义为指数）来定量成像瓦尔堡效应（IWE）；并且已经证明IWE对于区分脑肿瘤和脑肿瘤具有高度敏感性。在此申请中，我们正在寻求 NIH 的资金支持以推进该项目。 DMRS 成像开发通过：i) 集成硬件和软件开发以及超高场 MR技术可进一步提高信噪比（SNR）、光谱分辨率和时空分辨率ii) 在健康受试者和肿瘤患者中测试超高分辨率 DMRS 成像，并建立未来应用的量化模型和成像处理流程；以及 iii) 比较 DMRS 成像结果与生物样本的神经病理学和免疫组织化学结果相结合 DMRSI 测量值与脑肿瘤生物学特征之间的相关性。具有独特专业知识的跨学科研究团队已准备好全面开发这一高度创新且具有成本效益的神经影像对于神经肿瘤学的基础研究和临床应用至关重要。