Dynamic Nuclear Polarization MR Spectroscopic Imaging for Diagnosis and Treatment Response Assessment in Hepatocellular Carcinoma

在美国，肝细胞癌是癌症死亡率上升最快的原因。这个 大多数肝细胞癌患者在确诊时存在不治之症，尽管有针对性的批准 在接受治疗后，预期寿命仍然不到20个月。肝细胞癌的诊断及其对治疗的反应 治疗主要依靠成像生物标记物，它已经取代了基于组织的方法。最新研究 表明这些患者的悲观预后问题，至少在一定程度上是由于目前缺乏 临床影像模式在诊断肝细胞癌以及识别治疗后残留或复发的肝细胞癌中的作用。 肝细胞癌的临床影像诊断和治疗反应的评估是基于解剖学的。 成像特征往往无法识别出肝细胞癌或提供靶向治疗反应的功能性测量。 事实上，标准护理(SOC)对比增强(CE)MRI对小肝癌的敏感度可低至 20%同样，SOC成像对治疗反应的评估也不充分。解决这个问题 缺乏需要开发新的成像范例，提供肝细胞癌生物学的功能测量 以提高准确性、敏感性和特异性，并为治疗学的应用提供信息。 新的肝细胞癌功能成像策略的发展一直受到缺乏 可以根据相关的肝细胞癌生物学以及缺乏 具有代表性的动物模型。利用基因组编辑和代谢组学，我们的实验室已经证明 肝癌细胞对乳酸脱氢酶和NADPH依赖还原酶的基本依赖性 动态核极化~(13)C磁共振波谱有希望的成像靶标 成像(DNP-13C-MRSI)，一种新兴的成像技术。拟议的项目将建立在这一先前工作的基础上 研究DNP-13C-MRSI在以下方面的能力：1)提高诊断和治疗反应评估的准确性 与常规成像相比，SOC治疗后肝细胞癌的发生率和2)提供治疗选择的信息。 我们假设DNP-13C-MRSI提供了一种独特的技术，通过它可以利用基本的 肝癌细胞的酶依赖性并使功能分子成像能够用于诊断和治疗 响应评估。为了验证这一假设，拟议的项目将使用独特的肝细胞癌动物模型 我们实验室开发的目标有三：(1)优化DNP-13C-MRSI脉冲序列，使其能够 灵敏、准确、重复性好的原地肝细胞局部丙酮酸代谢测定 DNP-13C-MRSI诊断Hp1-13C-MRSI的敏感性、特异性和准确性。 丙酮酸摄取和代谢用于识别肝细胞癌；以及(3)确定DNP-13C-MRSI的准确性。 HP 1-13C-丙酮酸和/或1-13C-脱氢抗坏血酸(DHA)用于残留物的鉴定和表征 与SOC成像相比，TAE后的疾病/局部复发。拟议目标的实现情况 有可能改变肝细胞癌患者的成像和治疗，这是一种毁灭性的疾病。

Hepatocellular carcinoma (HCC) is the most rapidly rising cause of cancer mortality in the United States. The majority of patients with HCC present with incurable disease at diagnosis and, despite the approval of targeted therapies, life expectancy remains less than 20 months. The diagnosis of HCC as well as its response to treatment rely primarily on imaging biomarkers which have replaced tissue-based methods. Recent studies demonstrate that the dismal prognosis for these patients issues, at least in part, from deficiencies of current clinical imaging paradigms in diagnosing HCC as well as in identifying residual or recurrent HCC after treatment. Clinical imaging paradigms for HCC diagnosis and the assessment of treatment response are based on anatomic imaging features that often fail to identify HCCs or provide functional measures of response to targeted therapies. Indeed, the sensitivity of standard-of-care (SOC) contrast-enhanced (CE) MRI for small HCCs can be as low as 20%. Similarly, SOC imaging provides inadequate assessments of response to therapies. Addressing this deficiency requires the development of new imaging paradigms that provide functional measures of HCC biology to improve accuracy, sensitivity and specificity as well as inform the application of therapeutics. The development of novel functional imaging strategies for HCC has been limited by the absence of methodologies that can tailor imaging probe selection to the relevant HCC biology as well as a dearth of representative animal models. Using genome editing and metabolomics, our laboratory has demonstrated the fundamental dependence of HCC cells on lactate dehydrogenase and NADPH-dependent reductases to be promising imaging targets for Dynamic Nuclear Polarization 13Carbon Magnetic Resonance Spectroscopic Imaging (DNP-13C-MRSI), an emerging imaging technology. The proposed project will build on this prior work to study the ability of DNP-13C-MRSI to: 1) improve the accuracy of diagnosis and treatment response assessment of HCC following SOC therapies as compared to conventional imaging and 2) inform treatment selection. We hypothesize that DNP-13C-MRSI provides a unique technology through which to leverage fundamental enzymatic dependencies of HCC cells and enable functional molecular imaging for diagnosis and treatment response assessment. To test this hypothesis the proposed project will use unique animal models of HCC developed in our lab to pursue three aims: (1) to optimize a DNP-13C-MRSI pulse sequence that enables sensitive, accurate and reproducible measurements of regional pyruvate metabolism in autochthonous HCCs at high spatial resolution; (2) to determine the sensitivity, specificity and accuracy of DNP-13C-MRSI of HP 1-13C- pyruvate uptake and metabolism for identifying HCCs; and (3) to determine the accuracy of DNP-13C-MRSI of HP 1-13C-pyruvate and/or 1-13C-dehydroascorbic acid (DHA) for identifying and characterizing residual disease/local recurrence following TAE as compared to SOC imaging. The achievement of the proposed aims holds the potential to transform the imaging and treatment of patients with HCC, a devastating disease.