Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

从噪声成像扫描中恢复特征：溶解动态核极化（dDNP）超极化方法允许使用13C标记的内源代谢底物，如丙酮酸盐，在13C MRI中具有足够的信号增强，并允许使用13C MRI监测特定生化途径的代谢通量。现在在几个中心已经成为一种临床模式。尽管dDNP提供了数量级的信号增强，但在临床前和临床13C MRI研究中，信号往往不是最佳的，这使得酶通量的定量不太可靠。开发了一种数据驱动的动态hp13c磁共振光谱成像（MRSI）处理框架——张量秩截断图像增强（TRI），用于从噪声成像数据中恢复特征。在明确定义的临床前研究中验证了这种后处理方法后，现在在临床数据集中进行测试。使用从大脑、腹部和骨盆获得的患者数据集，我们研究了TRI的理论和应用。TRI为单元件配置提供了31倍的增益，这尤其改善了在许多情况下无法检测到的低信噪比[13C]碳酸氢盐和丙氨酸信号的量化。这使得首次从相同的数据集评估多种酶的活性成为可能。即使在次优实验条件下获得的数据集，包括延迟（114秒）注射（仅通过TRI获得8倍的信噪比），或具有挑战性的解剖或几何结构，如患有脑干肿瘤的儿科患者（使用TRI和WSVD联合获得8倍的信噪比），也可以观察到显著的信噪比增强。丙酮酸-乳酸转化升高、活检证实的癌症和mp-MRI病变之间的相关性改善，表明TRI恢复了定量诊断信息。后处理图像数据集的TRI方法可以恢复特征，从而更好地量化肿瘤中的酶活性，使诊断更加可靠。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。然而，尽管付出了巨大的努力，仍然缺乏具有足够特异性和体内活性的LDH抑制剂（LDHi）来确定LDH是否是可行的药物靶点。我们使用超极化13C MRI来开发体内药效学成像生物标志物来评估靶活性。我们描述了一种具有有效的，靶向的，体内活性的LDHi。利用超极化磁共振波谱成像（HPMRSI），我们证实了两种糖酵解性癌症模型MIA PaCa2和HT29的体内LDH抑制，并将LDH抑制的深度和持续时间与直接抗肿瘤活性联系起来。HPMRSI还揭示了在体内LDH抑制30分钟内发生的代谢重新连接，其中肿瘤中的丙酮酸被重定向到线粒体代谢。利用HPMRSI，我们发现抑制线粒体复合体1迅速将肿瘤丙酮酸重定向为乳酸。抑制线粒体复合体1和LDH均抑制代谢可塑性，导致体外代谢静止，体内肿瘤生长抑制。c)内源性代谢底物的代谢成像策略：肿瘤之间和肿瘤内部的代谢差异可能是癌症治疗结果的重要决定因素。然而，缺乏在体内无创地确定这些差异的方法。目前使用溶解DNP与13C MRI的超极化示踪剂是临床前和临床研究的唯一方法。然而，这种能力仅在有限的中心可用，这使得该方法的广泛传播具有挑战性。我们已经开发了一种降噪方法，允许13C MRI与内源性底物无超极化。以胰腺导管腺癌为模型，我们证明具有相似遗传背景的肿瘤异种移植物可以通过其不同的13C标记葡萄糖示踪剂代谢率来区分，通过使用新开发的噪声抑制技术可以在无超极化的情况下成像。使用这种方法，基于稳态代谢测量似乎具有相似代谢谱的癌症亚型可以彼此区分。13Cglucose成像的代谢图将乳酸生成和总体葡萄糖代谢定位到某些肿瘤的不同区域。这种肿瘤异质性在FDGPET中检测不到。这种方法的13C MRI使用13C标记内源性底物无超极化可能广泛传播。

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.