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

已建立的评估实体肿瘤治疗反应的指南是基于常规成像的 指标，如肿瘤大小和血管，旨在促进对 在灌流良好的微环境中以增殖细胞为靶点的系统性化疗药物。 肿瘤复发的一种新的成像表型表明，完全的放射学反应可能是 随后是不同的潜伏期，在较差的灌流微环境中没有可察觉的增长。这 成像表型突出了癌细胞调整其生长程序以适应其 微环境和对肿瘤休眠的影响，强调发展功能成像的重要性 使它们能够被发现的范例。 肝细胞癌的肝动脉化疗栓塞术(TACE)提供了一种 令人信服的临床表现与这种影像缺陷有关。TACE利用肝癌的血管生物学剥夺 肿瘤的营养物质，导致坏死；然而，只有44%的大的治疗皮损显示广泛 病理上的坏死，强调了肝癌细胞对营养剥夺的适应性反应。这种自适应 反应反映为在组织病理学上坏死区附近存在活的肿瘤细胞， 并且与在后续成像中经常观察到的潜伏期之后的快速复发是一致的。在……里面 临床前研究表明：1)在TACE诱导的缺血中存活的肝癌细胞被重新编程为 将葡萄糖碳向乳酸分流，为检测这些细胞提供独特的信号；2)基于 这种重新编程的动态核极化~(13)C-核磁共振波谱 肥大(HP)1-13C-丙酮酸的成像(DNP-13C-MRSI)使肝癌的检测更敏感 与标准护理(SOC)MRI相比，用于评估TACE反应的细胞；以及3)检测 TACE难治性细胞结构域将通过识别分子依赖性来指导靶向治疗。 我们假设HP 1-13C-丙酮酸的DNP-13C-MRSI提供了一种独特的技术，通过它可以 利用在TACE中存活的肝癌细胞的代谢重新编程并启用功能分子成像 用于患者有效的治疗反应评估。为了验证这一假设，提议的项目将继续 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 应用临床影像系统检测Hp1-13C-丙酮酸在肝细胞癌中的表达；(2a)测定DNP-13C-MRSI的敏感性 幽门螺杆菌1-13C-丙酮酸摄取和代谢用于确定完全应答患者的局部复发 根据目前的SOC成像反应标准衡量的TACE；以及(2b)确定DNP的准确性- Hp-1-13C-丙酮酸~(13)C-MRSI检测靶向代谢应激 肝细胞癌TACE治疗后的反应。拟议目标的实现具有转变的潜力 肝细胞癌是一种毁灭性的疾病，其影像和治疗。

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.