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

动态核偏振磁共振波谱成像用于肝细胞癌的诊断和治疗反应评估

基本信息

批准号：
10367551
负责人：
Terence P Gade
金额：
$ 58.05万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-05 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367551
关键词：
2,4-Dinitrophenol Achievement Address Aftercare Alanine Animal Model Ascorbic Acid BAY 54-9085 Biology Cancer Etiology Carbon Cells Clinic Clinical Trials Common Neoplasm Data Dehydroascorbic Acid Dependence Detection Development Diagnosis Disease Functional Imaging Glucose Image Imaging technology Inferior Ischemia Laboratories Lactate Dehydrogenase Life Expectancy Liver Magnetic Resonance Imaging Malignant Epithelial Cell Malignant Neoplasms Measurement Measures Metabolic Metabolism Methodology Methods Molecular and Cellular Biology NADP Nuclear Oxidation-Reduction Oxidoreductase Pathologic Patients Physiologic pulse Positron-Emission Tomography Primary carcinoma of the liver cells Prognosis Pyruvate Pyruvate Metabolism Pathway Recurrence Reproducibility Residual Tumors Residual state Resolution Selection for Treatments Sensitivity and Specificity Shunt Device Signal Transduction Stress Technology Testing Therapeutic Therapeutic Embolization Time Tissues Translating Tumor Burden United States Work aerobic glycolysis anatomic imaging base cancer cell cancer imaging clinical application clinical imaging contrast enhanced detection sensitivity diagnostic accuracy genome editing imaging biomarker imaging probe improved in vivo liver cancer model magnetic resonance spectroscopic imaging metabolic imaging metabolomics molecular imaging mortality novel patient prognosis response spectroscopic imaging standard of care targeted imaging targeted treatment treatment response treatment stratification tumor tumorigenesis uptake

项目摘要

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.

肝细胞癌（HCC）是美国癌症死亡率上升最快的原因。这大多数 HCC 患者在诊断时就表现出无法治愈的疾病，尽管靶向治疗已获得批准治疗后，预期寿命仍不足20个月。 HCC 的诊断及其应对措施治疗主要依赖于成像生物标志物，该标志物已取代基于组织的方法。最近的研究表明这些患者的不良预后问题至少部分是由于当前的缺陷造成的诊断 HCC 以及识别治疗后残留或复发性 HCC 的临床影像范例。 HCC 诊断和治疗反应评估的临床影像范式基于解剖学影像学特征通常无法识别 HCC 或无法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 对小型 HCC 的敏感性可低至 20%。同样，SOC 成像对治疗反应的评估不充分。解决这个问题缺陷需要开发新的成像范式，提供 HCC 生物学的功能测量提高准确性、敏感性和特异性，并为治疗方法的应用提供信息。 HCC 新型功能成像策略的开发因缺乏可以根据相关 HCC 生物学以及缺乏的情况定制成像探针选择的方法代表性动物模型。利用基因组编辑和代谢组学，我们的实验室已经证明肝癌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 碳磁共振波谱有前景的成像目标成像（DNP-13C-MRSI），一种新兴的成像技术。拟议的项目将建立在先前工作的基础上研究DNP-13C-MRSI的能力：1）提高诊断和治疗反应评估的准确性与传统影像学相比，SOC 治疗后 HCC 的发生率以及 2) 为治疗选择提供信息。我们假设 DNP-13C-MRSI 提供了一种独特的技术，通过该技术可以利用基本原理 HCC 细胞的酶依赖性，使功能性分子成像能够用于诊断和治疗反应评估。为了检验这一假设，拟议的项目将使用独特的 HCC 动物模型我们实验室开发的产品旨在实现三个目标：(1) 优化 DNP-13C-MRSI 脉冲序列，使对原发性 HCC 区域丙酮酸代谢进行灵敏、准确和可重复的测量高空间分辨率； (2)测定HP 1-13C-DNP-13C-MRSI的敏感性、特异性和准确性用于识别 HCC 的丙酮酸摄取和代谢； (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)，用于识别和表征残留物与 SOC 成像相比，TAE 后疾病/局部复发。拟议目标的实现具有改变 HCC（一种毁灭性疾病）患者的成像和治疗的潜力。