Translating Hyperpolarized 13C Metabolic MRI to Predict Renal Tumor Aggressiveness

项目总结： 该项目旨在将超极化(HP)13C丙酮酸磁共振成像作为一种创新的代谢成像技术应用于临床 肾肿瘤侵袭性的非侵入性预测方法，这是一个尚未满足的临床需求。我们的研究是直接的 对PAR 19-264的响应，该标准支持“优化、应用和验证新兴成像或 专门针对临床应用的生物标记物方法“，目标是”减少过度诊断“，以及 “区分致命性癌症和非致命性疾病”。我们的项目是受肾肿瘤发病率上升的推动， 这在很大程度上是由于影像的使用增加，偶然发现了许多局限性的肿瘤。这些 包括良性肾肿瘤和恶性肾细胞癌(RCC)。当前影像检查或活组织检查 不能可靠地区分良性肿瘤、低级别RCC和高级别RCC。诊断 含糊不清导致了对许多惰性肿瘤的过度诊断，这些肿瘤不必要地通过手术治疗 手术风险，更重要的是，增加慢性肾脏疾病和相关心血管疾病的风险。 值得注意的是，RCC检测的增加并没有转化为癌症特异性死亡的减少。因此， 有一个重要的未得到满足的新的成像标记的需求，可以改善风险分层 定位肾肿瘤，指导患者治疗。HP 13C MRI是一种新兴的成像技术， 允许对以前无法访问的代谢过程进行特定于途径的实时研究 成像。我们在原位肾细胞癌模型中的临床前数据表明，HP 13C丙酮酸盐MRI可以 定量映射通过乳酸脱氢酶途径增加的丙酮酸到乳酸的代谢，以及 与肾癌的存在及其侵袭性密切相关的可成像生物标志物。我们还有 论证了肾肿瘤患者HP13C丙酮酸动态磁共振成像的可行性，并具有良好的临床应用价值 肿瘤与正常肾脏的代谢对比。基于这些有希望的初步数据，我们现在 建议首次探讨HP13C丙酮酸MRI对局限性肾肿瘤危险分层的价值。 目的1-我们将优化用于评估肾肿瘤代谢的MRI采集策略。目标2-我们将 探讨HP 13C丙酮酸MRI对良性肿瘤、低度恶性肾细胞癌和 高等级农村信用社。我们还将比较HP 13C数据与先进的1H MRI和放射组学分析，并开发 用多参数模型评估其是否能提高预测效果。目标3-我们将确定可重复性 Hp 13C丙酮酸MRI对肾脏肿瘤的诊断价值，并对新的分析方法进行评价，以进一步提高其稳健性 对新陈代谢进行量化。该项目的成功完成将提供有关惠普价值的第一批数据 13C-丙酮酸核磁共振在预测肾肿瘤侵袭性方面的应用，将为今后更大规模的临床研究铺平道路。 HP 13C丙酮酸已经被证明是安全的，我们预计13C代谢成像标记物将是 集成到最先进的多参数MRI中，以减少目前对惰性肿瘤的过度诊断 同时能够及早发现侵袭性RCC，并帮助安全地选择患者进行积极监测。

Project summary: This project aims to clinically translate hyperpolarized (HP) 13C pyruvate MRI as an innovative metabolic imaging approach for noninvasive prediction of renal tumor aggressiveness, an unmet clinical need. Our study is in direct response to PAR 19-264 that supports “The optimization, application and validation of emerging imaging or biomarker approaches targeted specifically for clinical application”, with the goals to “reduce overdiagnosis”, and “identify lethal cancers from non-lethal disease”. Our project is motivated by the rising incidence of renal tumors, largely due to the increased utilization of imaging with incidental discovery of many localized tumors. These include both benign renal tumors and malignant renal cell carcinomas (RCCs). Current imaging or biopsies cannot reliably differentiate between benign tumors, low grade RCCs, and high grade RCCs. The diagnostic ambiguity has led to an overdiagnosis of many indolent tumors which are unnecessarily treated by surgery with surgical risks, and importantly, increased risk of chronic kidney disease and associated cardiovascular disease. Notably, the increased detection of RCCs has not translated into a decrease in cancer specific death. Therefore, there is a significant unmet need for novel imaging markers that can improve the risk stratification of localized renal tumors to guide patient management. HP 13C MRI is an emerging imaging technology that allows real-time pathway-specific investigation of metabolic processes that were previously inaccessible by imaging. Our pre-clinical data in orthotopic RCC tumor models have shown that HP 13C pyruvate MRI can quantitatively map the increased pyruvate-to-lactate metabolism via the lactate dehydrogenase pathway, an imageable biomarker which is strongly linked to the presence of RCC and its aggressiveness. We have also demonstrated the feasibility of acquiring dynamic HP 13C pyruvate MRI of renal tumors in patients, with excellent metabolic contrast between tumor and normal kidney. Building upon these promising preliminary data, we now propose to investigate for the first time the value of HP 13C pyruvate MRI for risk stratifying localized renal tumors. Aim 1- we will optimize the MRI acquisition strategies for renal tumor metabolic evaluation. Aim 2- we will investigate the value of HP 13C pyruvate MRI for differentiating between benign tumors, low grade RCCs, and high grade RCCs. We will also compare HP 13C data to advanced 1H MRI and radiomics analyses, and develop multi-parametric model to assess whether it can improve the prediction. Aim 3- we will determine the repeatability of HP 13C pyruvate MRI of renal tumors, and evaluate new analysis methods to further improve the robustness of metabolism quantification. Successful completion of this project will provide the first data on the value of HP 13C pyruvate MRI in predicting renal tumor aggressiveness, and will pave the way for future larger clinical studies. HP 13C pyruvate has already been shown to be safe, and we envision the 13C metabolic imaging markers to be incorporated into a state-of-the-art multi-parametric MRI to reduce the current overdiagnosis of indolent tumors while enabling the early detection of aggressive RCCs, and help safely select patients for active surveillance.