One-shot morphologic, hemodynamic and metabolic MR imaging of brain tumors

项目总结/摘要： 本项目的目标是验证临床上可行的，一次性对比增强，多参数MRI 一种使用单一的脑肿瘤形态学、血流动力学和代谢特征的方法 造影剂。对比增强（CE）MRI是指导几乎所有方面的临床成像标准， 脑肿瘤管理，包括手术活检/切除、放射治疗计划和治疗后 监测以进行反应评估。动态磁化率对比（DSC）MRI是一种补充 利用用于CE-MRI的造影剂的动态通过的技术， 肿瘤灌注图。在肿瘤病理生理学评估中未满足的临床需求是能够 常规检测缺氧及其演变。脑肿瘤表现出相当大的缺氧，这导致治疗 耐药，触发更具侵略性和侵入性的表型，被认为是一个潜在的治疗目标， 是总生存率的预后指标。临床上最广泛使用的询问缺氧的方法依赖于 PET放射性示踪剂，在脑肿瘤的背景下，需要多次扫描和注射， 常规CE-MRI和DSC-MRI。这种限制增加了成本、剂量和患者不适，同时降低了患者的耐受性。 效率和广泛使用的可能性，特别是在非学术社区医院， 患者不太可能经历多模态成像。因此，基于MRI的缺氧成像 方法可以显着提高脑的代谢特征和治疗管理 肿瘤患者。我们已经开发了2-硝基咪唑的GdDOTA单酰胺缀合物（一种公认的方法， 缺氧结合部分），称为GdDO 3 NI，其能够检测局部缺氧。我们假设 CE-MRI、DSC-MRI和缺氧数据可以在脑肿瘤中在一次成像会话中采集， 单次注射GdDO 3 NI可以帮助预测缺氧靶向治疗的结果。我们预计 动态GdDO 3 NI MRI的最佳采集和分析方案将提供区域性的缺氧图， 与哌莫硝唑IHC和FMISO PET共定位，将提供缺氧肿瘤的一致估计 各种技术之间的差距。为此，我们建议1）验证基于GdDO 3 NI的CE-MRI 和DSC-MRI在原位、人源性胶质瘤临床前模型中的应用，2）建立基于最佳GdDO 3 NI的 缺氧标测方案，并使用免疫组织化学（IHC）和临床可比PET进行验证 标记物和3）证明GdDO 3 NI预测对缺氧活化的前药的反应的潜力， evofosfamide。我们的创新，一次性，多参数策略代表了大脑的转型转变 肿瘤成像，可以实现基于病变形态，区域灌注和 代谢异质性所提出的一次性治疗策略也可以应用于脑外癌症， 增加受本研究影响的患者范围以及将GdDO 3 NI转化为临床的可行性。

PROJECT SUMMARY/ABSTRACT: The goal of this project is to validate a clinically feasible, one-shot contrast-enhanced, multiparametric MRI approach for mapping the morphologic, hemodynamic and metabolic features of brain tumors using a single contrast agent. Contrast-enhanced (CE) MRI is the clinical imaging standard for guiding nearly all aspects of brain tumor management, including surgical biopsy/resection, radiation treatment planning, and post-treatment surveillance for response assessment. Dynamic susceptibility contrast (DSC) MRI is a complementary technique that leverages the dynamic passage of the contrast agents utilized for CE-MRI in order to provide maps of tumor perfusion. An unmet clinical need in the assessment of tumor pathophysiology is the ability to routinely detect hypoxia and its evolution. Brain tumors exhibit considerable hypoxia which leads to therapy resistance, triggers more aggressive and invasive phenotypes, is considered a potential therapeutic target, and is prognostic of overall survival. The most widely used method for interrogating hypoxia in the clinic relies on PET radiotracers, which, in the context of brain tumors, necessitates multiple scans and injections in addition to routine CE-MRI and DSC-MRI. This limitation increases costs, dose and patient discomfort, while reducing efficiency and the likelihood of widespread use, particularly in non-academic community hospitals where patients are unlikely to undergo multi-modality imaging. Consequently, an MRI-based hypoxia imaging approach could significantly enhance the metabolic characterization and therapeutic management of brain tumor patients. We have developed a GdDOTA monoamide conjugate of 2-nitroimidazole (a well-established hypoxia binding moiety), termed GdDO3NI, that enables detection of regional hypoxia. We hypothesize that CE-MRI, DSC-MRI and hypoxia data can be acquired in brain tumors in a single imaging session following a single-injection of GdDO3NI and can help predict outcome of hypoxia targeted therapy. We anticipate that optimal acquisition and analysis protocols for dynamic GdDO3NI MRI will provide hypoxia maps that regionally colocalize with pimonidazole IHC and FMISO PET and will provide congruous estimates of hypoxic tumor fraction between the various techniques. Towards this end we propose to 1) validate GdDO3NI based CE-MRI and DSC-MRI in orthotopic, human-derived glioma preclinical models, 2) establish optimal GdDO3NI based hypoxia mapping protocols and validate using immunohistochemistry (IHC) and clinically comparable PET markers and 3) demonstrate the potential of GdDO3NI to predict response to a hypoxia activated prodrug, evofosfamide. Our innovative, one-shot, multi-parametric strategy represents a transformational shift in brain tumor imaging that could enable personalized therapy based on lesion morphology, regional perfusion and metabolic heterogeneity. The proposed one-shot strategy could also be translated to cancers outside the brain, increasing the range of patients impacted by this research and feasibility of translating GdDO3NI to the clinic.