DNP-MRSI for the Detection of Latent, Treatment-Resistant Cellular Domains in HCC

DNP-MRSI 用于检测 HCC 中潜在的、治疗耐药的细胞结构域

基本信息

批准号：
10436006
负责人：
Terence P Gade
金额：
$ 41.61万
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：
2022-09-09 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436006
关键词：
2,4-Dinitrophenol Achievement Alanine Biology Blood Vessels Cancer Prognosis Cancer Survivor Carbon Cells Chemoembolization Chronic Chronic Disease Clinic Clinical Clinical Research Dependence Detection Development Disease Early Diagnosis Environment Extensive Necrosis Functional Imaging Glucose Goals Growth Guidelines Hepatic Histology Histopathology Human Image Imaging Techniques Imaging technology In complete remission Incidence Inferior Ischemia Lesion Magnetic Resonance Imaging Magnetism Malignant Epithelial Cell Malignant Neoplasms Measurement Measures Metabolic Metabolic stress Metabolism Molecular Necrosis Neoplasm Metastasis Nuclear Nutrient Pathology Patients Phase Phenotype Physiologic pulse Positron-Emission Tomography Primary carcinoma of the liver cells Prognosis Proliferating Protocols documentation Pyruvate Recurrence Refractory Residual Cancers Residual state Resistance Shunt Device Signal Transduction Solid Neoplasm Technology Testing Time Translating United States Work aerobic glycolysis base biological adaptation to stress cancer cell cancer imaging clinical application clinical imaging contrast enhanced detection sensitivity effective therapy follow-up imaging approach imaging system improved in vivo indexing magnetic resonance spectroscopic imaging metabolic imaging molecular imaging neoplastic cell nutrient deprivation optimal treatments preclinical study programs radiological imaging respiratory response spectroscopic imaging standard of care success targeted cancer therapy targeted delivery targeted treatment therapeutic target treatment response tumor tumor growth uptake

项目摘要

Established guidelines for assessing response of solid tumors to therapy are based on conventional imaging indices, such as tumor size and vascularity, and were intended to facilitate a uniform assessment of response to systemically administered chemotherapeutics that target proliferating cells in a well-perfused microenvironment. An emerging imaging phenotype of tumor recurrence indicates that a complete radiographic response may be followed by variable periods of latency without perceptible growth in poorly perfused microenvironments. This imaging phenotype highlights the capability of cancer cells to adapt their growth program to their microenvironment and effect tumor dormancy and underscores the importance of developing functional imaging paradigms to enable their detection. Transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) provides a compelling clinical correlate to this imaging deficiency. TACE exploits the vascular biology of HCC to deprive tumors of nutrients, leading to necrosis; however, only 44% of large treated lesions demonstrate extensive necrosis on pathology, underscoring the adaptive response of HCC cells to nutrient deprivation. This adaptive response is reflected by the presence of viable tumor cells adjacent to regions of necrosis on histopathology, and is consistent with the rapid recurrence following a period of latency often observed on follow-up imaging. In preclinical studies, we demonstrated that: 1) HCC cells surviving TACE-induced ischemia are reprogrammed to shunt glucose carbons toward lactate, providing a unique signature for the detection of these cells; 2) based on this reprogramming, Dynamic Nuclear Polarization Magnetic-13Carbon-Magnetic Resonance Spectroscopic Imaging (DNP-13C-MRSI)of hyperoplarized (HP) 1-13C-pyruvate enables the more sensitive detection of HCC cells for response assessment to TACE as compared to standard-of-care (SOC) MRI; and 3) the detection of TACE-refractory cellular domains will inform targeted therapy by identifying molecular dependencies. We hypothesize that DNP-13C-MRSI of HP 1-13C-pyruvate provides a unique technology through which to leverage the metabolic reprogramming in HCC cells surviving TACE and enable functional molecular imaging for effective treatment response assessment in patients. To test this hypothesis the proposed project will pursue two primary aims: (1) to validate an optimized pulse sequence for in vivo hepatic arterial phase DNP-13C-MRSI of HP 1-13C-pyruvate in HCC using clinical imaging systems.; (2a) to determine the sensitivity of DNP-13C-MRSI of HP 1-13C-pyruvate uptake and metabolism for identifying local recurrence in patients with a complete response to TACE, as measured by current SOC imaging response criteria; and (2b) to determine the accuracy of DNP- 13C-MRSI of HP 1-13C-pyruvate to lactate and alanine for the detection of the targetable metabolic stress response in HCC cells following TACE. The achievement of the proposed aims holds the potential to transform the imaging and treatment of patients with HCC, a devastating disease.

评估实体瘤治疗反应的既定指南基于传统成像指数，例如肿瘤大小和血管分布，旨在促进对反应的统一评估在灌注良好的微环境中系统地施用靶向增殖细胞的化疗药物。肿瘤复发的新兴成像表型表明，完整的放射学反应可能是随后是不同的潜伏期，在灌注不良的微环境中没有明显的生长。这成像表型强调了癌细胞调整其生长程序以适应其自身情况的能力微环境和影响肿瘤休眠并强调开发功能成像的重要性范式来实现它们的检测。经动脉化疗栓塞术 (TACE) 为肝细胞癌 (HCC) 的治疗提供了新的途径与这种成像缺陷有令人信服的临床关联。 TACE 利用 HCC 的血管生物学来剥夺肿瘤缺乏营养，导致坏死；然而，只有 44% 的治疗大病灶表现出广泛的病理学上的坏死，强调了肝癌细胞对营养剥夺的适应性反应。这种自适应反应通过组织病理学上坏死区域附近存在活肿瘤细胞来反映，并且与随访成像中经常观察到的一段潜伏期后的快速复发相一致。在在临床前研究中，我们证明：1）在 TACE 诱导的缺血中幸存的 HCC 细胞被重新编程为将葡萄糖碳分流至乳酸，为这些细胞的检测提供独特的特征； 2）基于这种重编程，动态核极化磁13碳磁共振波谱超显像 (HP) 1-13C-丙酮酸盐成像 (DNP-13C-MRSI) 能够更灵敏地检测 HCC 与标准护理 (SOC) MRI 相比，用于评估 TACE 反应的细胞； 3) 检测 TACE 难治性细胞域将通过识别分子依赖性为靶向治疗提供信息。我们假设 HP 1-13C-丙酮酸的 DNP-13C-MRSI 提供了一种独特的技术，通过该技术利用 TACE 中存活的 HCC 细胞的代谢重编程并实现功能性分子成像对患者进行有效的治疗反应评估。为了检验这一假设，拟议项目将追求两个主要目标：(1) 验证体内肝动脉相 DNP-13C-MRSI 的优化脉冲序列使用临床成像系统检测 HCC 中的 HP 1-13C-丙酮酸。 (2a) 测定DNP-13C-MRSI的灵敏度 HP 1-13C-丙酮酸摄取和代谢，用于识别完全缓解患者的局部复发根据当前 SOC 成像响应标准测量的 TACE； (2b) 确定 DNP 的准确性 HP 1-13C-丙酮酸到乳酸和丙氨酸的 13C-MRSI 用于检测目标代谢应激 TACE 后 HCC 细胞的反应。实现拟议目标具有变革的潜力肝细胞癌（一种毁灭性疾病）患者的影像学检查和治疗。