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

脑肿瘤的一次性形态学、血流动力学和代谢 MR 成像

• 批准号: 10316545
• 负责人: Vikram D. Kodibagkar
• 金额: $ 60.38万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316545
• 关键词: Address; Aftercare; Agreement; Animals; Binding; Biopsy; Blood Volume; Brain; Brain Neoplasms; Cell Density; Cell Proliferation; Cells; Clinic; Clinical; Community Hospitals; Contrast Media; Data; Detection; Dose; Europe; Evolution; Excision; Exhibits; Functional Imaging; Functional disorder; Glioma; Goals; Healthcare; Heterogeneity; Human; Hypoxia; Image; Imaging Techniques; Immunohistochemistry; Injections; Lesion by Morphology; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Metabolic; Methodology; Methods; Mission; Molecular Target; Morphology; Multimodal Imaging; Operative Surgical Procedures; Patients; Perfusion; Phenotype; Physiological; Pimonidazole; Population; Positron-Emission Tomography; Pre-Clinical Model; Predisposition; Prodrugs; Protocols documentation; Public Health; Radiation therapy; Recurrence; Regional Perfusion; Reporting; Research; Scanning; Site; Techniques; Therapeutic; Translating; United States National Institutes of Health; azomycin; base; blood-brain barrier disruption; brain tumor imaging; cancer imaging; clinical imaging; contrast enhanced; cost; fluorescence imaging; hemodynamics; imaging approach; innovation; neuro-oncology; outcome prediction; patient derived xenograft model; personalized medicine; predicting response; prognostic of survival; radiotracer; response; targeted treatment; therapeutic target; therapy resistant; treatment effect; treatment planning; tumor; tumor growth; tumor hypoxia

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.

项目概要/摘要： 该项目的目标是验证一种临床上可行的一次性对比增强多参数 MRI 使用单一方法绘制脑肿瘤的形态、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 监测反应评估。动态磁化率对比 (DSC) MRI 是一种补充 该技术利用用于 CE-MRI 的造影剂的动态通道来提供 肿瘤灌注图。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。脑肿瘤表现出严重缺氧，导致治疗 耐药性，引发更具攻击性和侵入性的表型，被认为是潜在的治疗靶点，并且 是总体生存的预后。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，在脑肿瘤的情况下，还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态成像。因此，基于 MRI 的缺氧成像 该方法可以显着增强大脑的代谢特征和治疗管理 肿瘤患者。我们开发了 2-硝基咪唑（一种成熟的 缺氧结合部分），称为 GdDO3NI，能够检测局部缺氧。我们假设 CE-MRI、DSC-MRI 和缺氧数据可在脑肿瘤中通过一次成像获取 单次注射GdDO3NI可以帮助预测缺氧靶向治疗的结果。我们预计 动态 GdDO3NI MRI 的最佳采集和分析协议将提供局部缺氧图 与哌莫硝唑 IHC 和 FMISO PET 共定位，并将提供缺氧肿瘤的一致估计 各种技术之间的分数。为此，我们建议 1) 验证基于 GdDO3NI 的 CE-MRI 和 DSC-MRI 在原位、人源性神经胶质瘤临床前模型中，2) 建立基于 GdDO3NI 的最佳 缺氧图谱方案并使用免疫组织化学 (IHC) 和临床可比的 PET 进行验证 标记物和 3) 证明 GdDO3NI 预测对缺氧激活前药的反应的潜力， 依伏磷酰胺。我们的创新、一次性、多参数策略代表了大脑的变革性转变 肿瘤成像可以根据病变形态、区域灌注和情况进行个性化治疗 代谢异质性。所提出的一次性策略也可以转化为脑外癌症， 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。