Enhanced Deuterium Metabolic Imaging (DMI) of Metabolic Reprogramming in Brain Tumors

脑肿瘤代谢重编程的增强氘代谢成像 (DMI)

• 批准号: 10593853
• 负责人: Daniel M Spielman
• 金额: $ 61.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593853
• 关键词: Affect; Anatomy; Brain; Brain Neoplasms; Brain scan; Cancer Cell Growth; Cells; Central Nervous System; Clinical; Coin; Consumption; Data; Data Set; Detection; Deuterium; Development; Diagnostic; Energy Metabolism; Exhibits; Gases; Glioblastoma; Glioma; Glucose; Glycolysis; Goals; Half-Life; Human; Image; Imaging Device; Imaging Techniques; Inhalation; Joint repair; Label; Lesion; Machine Learning; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Noise; Normal tissue morphology; Oxidative Phosphorylation; Oxygen Consumption; Patients; Performance; Phenotype; Pilot Projects; Play; Positron-Emission Tomography; Process; Production; Protocols documentation; Pyruvate; Radioactive; Reporting; Resolution; Role; Scanning; Signal Transduction; Sum; System; Techniques; Testing; Therapeutic; Tissues; Training; Tumor Markers; Warburg Effect; brain tumor imaging; clinical translation; convolutional neural network; data acquisition; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; image processing; imaging approach; imaging study; improved; in vivo; in vivo imaging; innovation; magnetic resonance spectroscopic imaging; metabolic imaging; multimodality; non-invasive imaging; novel; novel therapeutic intervention; novel therapeutics; rapid growth; reconstruction; signal processing; simulation; timeline; tool; treatment response; tumor; tumor growth; tumor metabolism; virtual

Abstract Deuterium metabolic imaging (DMI) is an emerging MRI technique whereby deuterated substrates and their metabolic products are imaged in vivo. A primary application is the study of energy metabolism, a fundamental process for virtually all cells in the body. In particular, glucose (Glc) metabolism plays a critical role in cancer, with two key metrics of tumor metabolism being total glucose consumption and the relative fraction of Glc undergoing glycolysis (GLY) versus oxidative phosphorylation (OXPHOS). In contrast to normal tissues, most cancers exhibit a preponderance of GLY over OXPHOS. Known as the Warburg effect or, more generally metabolic reprogramming, these alterations are particularly pronounced in glioma and other brain tumors. Elevated GLY in high-grade brain tumors has been shown to be a marker of tumor growth and aggressiveness. From a therapeutic perspective, studies strongly support that this Warburg phenotype is necessary and sufficient for the cancer process, which provides the framework of a highly novel therapeutic strategy targeted at affecting these metabolic pathways. We contend that clinical translation is presently impeded not so much by a lack of agents, but by the difficulty in measuring these fundamental aspects of tumor metabolism in vivo. Of the available imaging techniques, 18F-FDG-PET is well-established for imaging glucose uptake, whereas robust in vivo measurements of GLY and OXPHOS are considerably more challenging. Triple 15O-PET can be used to assess oxygen consumption (and hence OXPHOS) but is clinically problematic due to the 2-min half- life of 15O and the challenges of coordinating multiple inhaled radioactive gases. MRI of hyperpolarized 13C- labeled pyruvate has been shown capable of assessing tumor GLY/OXPHOS ratios; however, this technique is very expensive with limited availability and unique challenges. More recently, the feasibility of using conventional 2H MRSI of deuterated glucose to measure both GLY and OXPHOS has been successfully demonstrated. Given the ubiquity of 3T scanners, we contend that 3T DMI would have maximal clinical impact, and initial results for the human brain reported at 4T, in combination with our own 3T DMI data, indicate limited spatial resolution, low SNR, and correspondingly long scan times are the primary limitations. This technical development project will address these challenges by enhancing DMI via the incorporation of multimodal information. Noting that 1H MRI and FDG-PET share significant mutual anatomic and metabolic information with DMI, we propose to significantly enhance 3T DMI using signal processing and machine learning approaches analogous to techniques using MRI to enhance FDG-PET resolution and SNR. The overall goal is to demonstrate enhanced DMI acquisitions and image processing pipelines for maximal clinical impact, with the initial application being the imaging of the Warburg effect in brain tumors.

摘要 氘代谢成像（DIM）是一种新兴的MRI技术，其中氘代底物和 它们的代谢产物在体内成像。一个主要的应用是研究能量代谢， 这是身体所有细胞的基本过程。特别地，葡萄糖（Glc）代谢在代谢中起关键作用。 在癌症中的作用，肿瘤代谢的两个关键指标是总葡萄糖消耗和相对葡萄糖消耗。 经历糖酵解（GLY）与氧化磷酸化（OXPHOS）的Glc部分。与正常相比， 在组织中，大多数癌症表现出GLY超过OXPHOS的优势。被称为“瓦尔堡效应”， 通常代谢重编程，这些改变在神经胶质瘤和其他脑组织中特别明显。 肿瘤的高级别脑肿瘤中升高的GLY已被证明是肿瘤生长的标志物， 侵略性从治疗的角度来看，研究强烈支持这种瓦尔堡表型是 这是癌症过程所必需和充分的，它提供了一种高度新颖的治疗方法的框架。 旨在影响这些代谢途径的策略。我们认为，临床翻译目前是 阻碍因素与其说是缺乏代理人，不如说是难以衡量这些基本方面 体内肿瘤代谢。 在可用的成像技术中，18F-FDG-PET被公认用于葡萄糖摄取成像，而 GLY和OXPHOS的体内稳健测量具有相当大的挑战性。三重15 O-PET可以是 用于评估耗氧量（因此OXPHOS），但由于2分钟半- 15 O的寿命和协调多种吸入放射性气体的挑战。超极化13 C- 标记的丙酮酸盐已经显示出能够评估肿瘤GLY/OXPHOS比率;然而，这种技术 非常昂贵，可用性有限，并且面临独特的挑战。最近，使用 用氘代葡萄糖的常规2 H MRSI测量GLY和OXPHOS已成功 演示。鉴于3 T扫描仪的普遍性，我们认为3 T扫描仪将具有最大的临床影响， 在4 T下报告的人类大脑的初步结果，结合我们自己的3 T数据， 空间分辨率、低SNR和相应的长扫描时间是主要的限制。本技术 一个发展项目将通过纳入多式联运来加强可持续发展， 信息.注意到1H MRI和FDG-PET共享重要的相互解剖和代谢信息 有了3 T，我们建议使用信号处理和机器学习来显著增强3 T的3 T能力。 方法类似于使用MRI的技术来增强FDG-PET分辨率和SNR。总的目标是 展示增强的DMI采集和图像处理管道，以实现最大的临床影响， 最初的应用是脑肿瘤中的瓦尔堡效应的成像。