Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

奥豪瑟增强磁共振成像 (OMRI)

• 批准号: 10262094
• 负责人: Murali Krishna
• 金额: $ 119.11万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262094
• 关键词: 2,4-Dinitrophenol; Abdomen; Aftercare; Alanine; Anatomy; Bicarbonates; Biochemical; Biochemical Pathway; Biopsy; Brain; Brain Stem Neoplasms; Cancer Model; Cell Nucleus; Chemicals; Clinical; Clinical Research; Complex; Data; Data Set; Dependence; Diagnosis; Diagnostic; Drug Targeting; Elements; Enzymes; Generations; Genetic; Geometry; Glucose; Image; Image Enhancement; In Vitro; Injections; Label; Lactate Dehydrogenase; Lesion; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Maps; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modality; Modeling; Monitor; Nature; Noise; Nuclear; Pancreatic Ductal Adenocarcinoma; Patients; Pelvis; Pharmacodynamics; Physiology; Production; Protons; Pyruvate; Recovery; Scanning; Signal Transduction; Specificity; Techniques; Testing; Time; Tracer; Treatment outcome; Water; aerobic glycolysis; base; cancer subtypes; cancer therapy; density; enzyme activity; glucose metabolism; imaging biomarker; improved; in vivo; inhibitor/antagonist; magnetic resonance spectroscopic imaging; metabolic imaging; metabolic profile; mitochondrial metabolism; molecular imaging; pediatric patients; pre-clinical; pre-clinical research; preclinical study; spectroscopic imaging; theories; treatment effect; treatment response; tumor; tumor growth; tumor heterogeneity; tumor xenograft

Recovery of features from noisy imaging scans: Dissolution Dynamic Nuclear Polarization (dDNP) method of hyperpolarization allowed the use of 13C labeled endogenous metabolic substrates such as pyruvate to have sufficient signal enhancement in 13C MRI and permit monitoring metabolic fluxes of specific biochemical pathways using 13C MRI. It is now a clinical modality in several centers. In spite of the orders of magnitude signal enhancement provided by dDNP, often times in preclinical and clinical 13C MRI studies the signals are suboptimal making the quantification of enzyme fluxes less reliable. A data-driven processing framework for dynamic HP 13C MR spectroscopic imaging (MRSI), Tensor Rank truncation Image enhancement (TRI) was developed to recover features from noisy imaging data. After validating this postprocessing approach in well defined preclinical studies, it is now tested in clinical datasets. Using patient data sets acquired from the brain, abdomen, and pelvis, we examined the theory and application of TRI. TRI provided a 31-fold gain for single-element configurations, which particularly improved quantification of the lowerSNR[13C]bicarbonate and alanine signals that were otherwise not detectable in many cases. This allowed for the first time assessment of multiple enzyme activities from the same data sets. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8 fold SNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (fold using combined TRI and WSVD). Improved correlation between elevated pyruvate-to-lactate conversion, biopsy-confirmed cancer, and mp-MRI lesions demonstrated that TRI recovered quantitative diagnostic information. The TRI method of postprocessing image data sets has allowed recovery of features to make better quantification of enzyme activities in tumors making diagnoses more reliable. b) In vivo pharmacodynamic assessment of new generation LDHA inhibitors: The reliance of many cancers on aerobic glycolysis has stimulated efforts to develop lactate dehydrogenase (LDH) inhibitors. However, despite significant efforts, LDH inhibitors (LDHi) with sufficient specificity and in vivo activity to determine whether LDH is a feasible drug target are lacking. We used hyperpolarized 13C MRI to develop an in vivo pharmacodynamic imaging biomarker to assess the ontarget activity. We describe an LDHi with potent, on target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HPMRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa2 and HT29, and we correlate depth and duration of LDH inhibition with direct antitumor activity. HPMRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HPMRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition of both mitochondrial complex 1 and LDH suppresses metabolic plasticity, causing metabolic quiescence in vitro and tumor growth inhibition in vivo. c) Metabolic Imaging strategies with endogenous metabolic substrates: Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences noninvasively in vivo is lacking. Currently hyperpolarized tracers using dissolution DNP with 13C MRI is the only method available for preclinical and clinical research. However, this capability is available only in limited centers making the method's dissemination widely challenging. We have developed a noise reduction approach which allows 13C MRI with endogenous substrates without hyperpolarization, Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from 13Cglucose imaging localized lactate production and overall glucose metabolism to different regions of some tumors. Such tumor heterogeneity would be not detectable in FDGPET. This method of 13C MRI using 13C labeled endogenous substrates without hyperpolarization potentially widely disseminatable.

从嘈杂的成像扫描中恢复特征：超极化的溶解动态核极化（DDNP）方法允许使用13C标记的内源代谢底物（例如丙酮酸）在13C MRI中具有足够的信号增强，并允许使用13C MRI的特定生物化学途径的代谢通量进行足够的信号增强。现在，它是几个中心的临床方式。尽管DDNP提供了数量级信号增强的顺序，但通常在临床前和临床13C MRI研究中，信号的次优地，使酶通量的定量较低。开发了用于动态HP 13C MR光谱成像（MRSI）的数据驱动的处理框架，张量级截断图像增强（TRI）是从嘈杂的成像数据中恢复特征的。在验证了定义明确的临床前研究中的这种后处理方法之后，现在在临床数据集中进行了测试。使用从大脑，腹部和骨盆中获取的患者数据集，我们检查了TRI的理论和应用。 TRI为单一元素构型提供了31倍的增益，这特别改善了对降低[13C]碳酸氢盐和丙氨酸信号的定量，在许多情况下否则无法检测到。这允许首次评估来自相同数据集的多种酶活性。对于即使在次优实验条件下获得的数据集，也可以观察到大量的SNR增强功能，包括延迟（114 s）注射（仅由TRI获得8倍SNR的增益），或者是出于挑战性解剖学或几何形状，例如使用脑干肿瘤的儿科患者（使用TRI和WSVD折叠）。丙酮酸升高到乳酸转化率，活检确认的癌症和MP-MRI病变之间的相关性提高了，表明TRI恢复了定量诊断信息。后处理图像数据集的TRI方法允许恢复特征，以更好地量化肿瘤中的酶活性，从而使诊断更可靠。 b）新一代LDHA抑制剂的体内药效学评估：许多癌症对有氧糖酵解的依赖刺激了开发乳酸脱氢酶（LDH）抑制剂的努力。但是，尽管做出了巨大的努力，但LDH抑制剂（LDHI）具有足够的特异性和体内活性，以确定LDH是否缺乏可行的药物靶标。我们使用超极化的13C MRI开发体内药效学成像生物标志物来评估安大略活性。我们描述了具有有效目标的LDHI体内活性。使用超极化磁共振光谱成像（HPMRSI），我们在两个糖酵解癌模型（MIA PACA2和HT29）中证明了体内LDH抑制作用，并将LDH抑制的深度和持续时间与直接抗肿瘤活性相关联。 HPMRSI还揭示了一种代谢重新布线，在LDH抑制后30分钟内发生在体内，其中肿瘤中的丙酮酸被重定向到线粒体代谢。使用HPMRSI，我们表明线粒体复合物的抑制1迅速将丙酮酸肿瘤转向乳酸。抑制线粒体复合物1和LDH抑制了代谢可塑性，从而导致体外代谢静止，并在体内抑制肿瘤生长。 c）内源代谢底物的代谢成像策略：肿瘤之间和内部的代谢差异可能是癌症治疗结果的重要决定因素。但是，缺乏确定这些差异在体内无创的方法。目前，使用溶解DNP和13C MRI的超极化示踪剂是临床前和临床研究的唯一方法。但是，此功能只有在有限的中心才能获得，这使该方法的传播广泛挑战。我们已经开发了一种减少降噪方法，该方法允许使用胰腺导管腺癌的内源性底物进行13C MRI，并允许使用胰腺导管性腺癌作为模型，我们证明，具有相似遗传背景的肿瘤异种移植物可以通过使用新的频率来抑制量子化的13c标记的频率imporliation的遗传背景来区分它们的遗传背景的差异。使用这种方法，可以彼此区分基于稳态代谢测量的代谢特征的癌症亚型。来自13cglucose成像的代谢图局部乳酸产生和总体葡萄糖代谢到某些肿瘤的不同区域。这种肿瘤异质性在FDGPET中无法检测到。这种13C MRI的方法使用13C标记的内源性底物，而没有超极化可能会广泛散布。