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

项目摘要/摘要： 该项目的目标是验证一种临床上可行的、单次增强的、多参数的磁共振成像。 脑肿瘤的形态、血流动力学和代谢特征的单一成像方法 造影剂。对比度增强(CE)MRI是临床影像标准，用于指导几乎所有方面的 脑肿瘤管理，包括手术活检/切除、放射治疗计划和治疗后 监视以进行响应评估。动态磁化率对比(DSC)MRI是一种补充 该技术利用用于CE-MRI的造影剂的动态通过，以便提供 肿瘤灌注图。在肿瘤病理生理学评估中一个尚未得到满足的临床需求是能够 定期检测缺氧及其演变情况。脑肿瘤表现出大量的低氧，这导致了治疗 耐药性，触发更多侵袭性和侵袭性表型，被认为是潜在的治疗靶点，以及 是总存活率的预测指标。临床上最广泛使用的询问缺氧的方法是依靠 PET放射性示踪剂，在脑瘤的情况下，需要进行多次扫描和注射 至常规的CE-MRI和DSC-MRI。这种限制增加了成本、剂量和患者的不适，同时减少了 效率和广泛使用的可能性，特别是在非学术社区医院 患者不太可能接受多模式成像。因此，基于MRI的低氧成像 方法可以显著提高脑的代谢特征和治疗管理 肿瘤患者。我们已经开发出了2-硝基咪唑的GdDOTA单酰胺结合物(一种公认的 缺氧结合部分)，称为GdDO3NI，能够检测局部缺氧。我们假设 脑肿瘤的CE-MRI、DSC-MRI和缺氧数据可以在一次成像会议中获得 单次注射GdDO3NI有助于预测低氧靶向治疗的结果。我们预料到 动态GdDO3NI MRI的最佳采集和分析方案将提供地区性低氧地图 与匹莫硝唑IHC和FMISO PET共同定位将提供对缺氧性肿瘤的一致估计 不同技术之间的分数。为此，我们建议1)验证基于GdDO3NI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GdDO3NI的最优模型 应用免疫组织化学(IHC)和临床可比PET进行低氧标测的方法和验证 标记物和3)证明GdDO3NI预测对缺氧激活的前体药物的反应的潜力， 依福福胺。我们的创新、一次性、多参数策略代表着大脑的变革性转变 肿瘤成像，可以基于病变形态、区域灌注和 代谢异质性。提议的一次性策略也可以转化为脑部以外的癌症， 扩大受这项研究影响的患者范围以及将GdDO3NI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.