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

肝细胞癌（HCC）是美国癌症死亡率上升最快的原因。的 大多数HCC患者在诊断时患有不治之症，尽管批准了靶向治疗， 治疗后，预期寿命仍然不到20个月。肝癌的诊断及其对化疗的反应 治疗主要依赖于成像生物标志物，其已经取代了基于组织的方法。最近的研究 这表明，这些患者的预后不佳的问题，至少部分是由于目前的缺陷， 临床影像学诊断HCC以及识别治疗后残留或复发HCC的范例。 HCC诊断和治疗反应评估的临床影像学范例是基于解剖学基础上的。 这些成像特征通常不能识别HCC或提供对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HCC的敏感性可以低至 百分之二十同样，SOC成像无法充分评估对治疗的反应。解决这一 这一缺陷需要开发新的成像范式来提供肝癌生物学的功能测量 以提高准确性、灵敏度和特异性，并为治疗的应用提供信息。 HCC的新功能成像策略的发展受到缺乏以下因素的限制： 可以根据相关HCC生物学定制成像探针选择的方法以及缺乏 代表性动物模型。利用基因组编辑和代谢组学，我们的实验室已经证明了 HCC细胞对乳酸脱氢酶和NADPH依赖性还原酶的基本依赖性， 动态核极化~（13）C磁共振波谱成像的前景 成像（DNP-13 C-MRSI），一种新兴的成像技术。拟议的项目将在这项先前工作的基础上， 研究DNP-13 C-MRSI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HCC的发生率; 2）告知治疗选择。 我们假设DNP-13 C-MRSI提供了一种独特的技术，通过这种技术可以利用基本的 HCC细胞的酶依赖性，并使诊断和治疗的功能分子成像成为可能 反应评估。为了验证这一假设，拟议的项目将使用独特的HCC动物模型 在我们的实验室开发追求三个目标：（1）优化DNP-13 C-MRSI脉冲序列，使 灵敏、准确和可重复地测量本地HCC中的局部丙酮酸代谢 （2）确定DNP-13 C-MRSI对HP 1- 13 C-1的敏感性、特异性和准确性。 用于鉴定HCC的丙酮酸摄取和代谢;和（3）确定DNP-13 C-MRSI的准确性， HP 1- 13 C-丙酮酸盐和/或1- 13 C-脱氢抗坏血酸（DHA）用于鉴别和表征残留物 与SOC成像相比，TAE后的疾病/局部复发。实现拟议目标 它有可能改变HCC患者的成像和治疗，HCC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.