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标记的内源性代谢底物(如丙酮酸)在13C MRI中有足够的信号增强，并允许使用13C MRI监测特定生化途径的代谢通量。它现在是几个中心的临床模式。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，信号往往是次优的，这使得酶通量的定量变得不那么可靠。提出了一种用于动态HP 13C磁共振波谱成像(MRSI)的数据驱动处理框架--张量秩截断图像增强(TRI)，以从噪声成像数据中恢复特征。在定义明确的临床前研究中验证了这种后处理方法之后，现在它在临床数据集中进行了测试。使用从大脑、腹部和骨盆获取的患者数据集，我们检查了TRI的理论和应用。TRI为单元素配置提供了31倍的增益，这特别改善了对低信噪比[13C]碳酸氢盐和丙氨酸信号的量化，否则在许多情况下无法检测到。这使得第一次可以从相同的数据集评估多种酶的活性。对于即使在次优实验条件下获得的数据集，也观察到显著的SNR增强，包括延迟(114 S)注射(仅由TRI获得8倍的SNR增益)，或者从具有挑战性的解剖学或几何学中获得，例如在患有脑干肿瘤的儿科患者的情况下(使用TRI和WSVD相结合的折叠)。丙酮酸到乳酸转化率升高、活检证实的癌症和MP-MRI损伤之间相关性的改善表明，TRI恢复了定量诊断信息。对图像数据集进行后处理的TRI方法允许恢复特征，以便更好地量化肿瘤中的酶活性，从而使诊断更可靠。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，尽管进行了大量的努力，但缺乏具有足够的特异性和体内活性来确定LDH是否是可行的药物靶点的LDH抑制剂。我们使用超极化13C核磁共振技术开发了体内药效学成像生物标记物来评估OnTarget的活性。我们描述了一种具有强大的靶向体内活性的LDHi。利用超极化磁共振波谱成像(HPMRSI)，我们在体内证明了两种糖酵解肿瘤模型MIA PaCa2和HT29对LDH的抑制作用，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还揭示了体内LDH抑制后30分钟内发生的代谢重排，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可以迅速将肿瘤丙酮酸重新定向为乳酸。抑制线粒体复合体1和LDH都会抑制代谢可塑性，导致体外代谢停滞和体内肿瘤生长抑制。C)使用内源性代谢底物的代谢成像策略：肿瘤之间和肿瘤内的代谢差异可能是癌症治疗结果的重要决定因素。然而，缺乏在体内非侵入性地确定这些差异的方法。目前，使用溶解DNP和13C MRI的超极化示踪剂是唯一可用于临床前和临床研究的方法。然而，这种能力仅在有限的中心可用，这使得该方法的传播具有广泛的挑战性。我们开发了一种降噪方法，允许具有内源性底物的13C MRI没有超极化，以胰腺导管腺癌为模型，我们证明了具有相似遗传背景的肿瘤移植瘤可以通过13C标记的葡萄糖示踪剂的不同代谢率来区分，利用新开发的噪声抑制技术可以在没有超极化的情况下进行成像。使用这种方法，根据稳态代谢测量，看起来具有相似代谢特征的癌症亚型可以相互区分。~(131)C葡萄糖成像的代谢图定位于某些肿瘤的不同区域的乳酸生成和总的葡萄糖代谢。这种肿瘤的异质性在FDGPET中是检测不到的。这种~(13)C磁共振成像方法使用~(13)C标记的内源性底物，没有超极化，具有潜在的广泛传播性。

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.