Dynamic multimodal imaging of tumor hypoxia and vascular profiles in glioblastoma

胶质母细胞瘤肿瘤缺氧和血管特征的动态多模态成像

• 批准号: 7789801
• 负责人: DAWEN ZHAO
• 金额: $ 17.24万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789801
• 关键词: Adjuvant; Adult; Affect; Angiogenesis Inhibitors; Bioluminescence; Blood - brain barrier anatomy; Blood Vessels; Brain; Cell Proliferation; Cell surface; Cells; Characteristics; Clinical; Clinical Treatment; Combined Modality Therapy; Data; Development; Disease-Free Survival; Drug Delivery Systems; Edema; Effectiveness; Evolution; Exhibits; Firefly Luciferases; Foundations; Future; Genetic; Glioblastoma; Glioma; Goals; Growth Factor; Heterogeneity; Human; Hypoxia; Hypoxia Inducible Factor; Image; Intervention; Knowledge; Label; Longitudinal Studies; Luciferases; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Intracranial Neoplasm; Malignant Neoplasms; Methods; Modeling; Monitor; Multimodal Imaging; Mus; Necrosis; Neuraxis; Outcome; Oxygen; PTEN gene; Pathologist; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Phenotype; Pimonidazole; Predisposition; Progression-Free Survivals; Proliferation Marker; Radiation; Radiation Tolerance; Radiation therapy; Radio; Reporter; Reporter Genes; Reporting; Resistance; Screening procedure; Series; Signal Transduction; Sodium Fluorescein; System; Techniques; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Treatment Protocols; Tumor Angiogenesis; Tumor Oxygenation; Vascular Endothelial Growth Factors; Weight; Xenograft procedure; angiogenesis; antiangiogenesis therapy; base; bevacizumab; blood oxygen level dependent; blood perfusion; chemotherapeutic agent; chemotherapy; cohort; density; design; driving force; improved; in vivo; mouse model; neoplastic cell; neovascular; new therapeutic target; novel; overexpression; public health relevance; radiation resistance; response; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Glioblastoma multiform (GBM) is the most common and lethal intracranial cancer, and highly resists to conventional multimodal therapies. These tumors are characterized by profound angiogenesis, disrupted blood-brain-barrier (BBB), vasogenic edema, as well as regions of hypoxia and necrosis, which have been shown to correlate negatively with local tumor control, disease free survival and overall survival. There is considerable anecdotal evidence that intra-tumoral hypoxia confers radiation resistance. However, in the absence of a reliable method of monitoring, in vivo, the dynamic intra-tumoral oxygen status, has remained untested in GBM. We have developed a genetic strategy to monitor intra-tumoral hypoxia using a bioluminescence reporter system. By introducing the Hypoxia-inducible-factor1a-firefly luciferase (HIF-1a-ODD-luc) to various GBM cells including the cells isolated from fresh GBM tumors of patient and enriched for the cell surface marker CD133, we will be able to monitor real-time tumor hypoxia in orthotopic GBM model by bioluminescent imaging (BLI). We also propose to develop MRI techniques based on an interleaved T2- (BOLD, blood oxygen level dependent) and T1- (tissue oxygen level dependent) weighted sequence for assessing tumor oxygenation, including baseline hypoxia, spatial heterogeneity and dynamics of response to interventions in orthotopic GBM model. Moreover, correlation of vascular perfusion, BBB status with hypoxia will be evaluated by dynamic susceptibility contrast (DSC) and Dynamic contrast enhanced (DCE) MRI. Recent gains in overall survival as well as progression free survival of GBM patients have been reported following adjuvant treatment with antiangiogenic and chemotherapeutic agents. However, the underlying mechanisms remain unclear. We hypothesize that in vivo multimodal imaging of tumor hypoxia and vasculature will enhance our understanding of pathophysiological mechanisms of effective antiangiogenesis and further facilitate optimization of combined radiotherapy or chemotherapy. The major goal of this project is to integrate multiple parameters of tumor hypoxia and vasculature acquired by multimodal imaging to correlate with tumor aggressiveness and understand pathophysiological mechanism underlying the clinical benefits from antiangiogenic treatment. The imaging findings will be correlated with histological and immunohistochemical studies of perfusion, vascular density and hypoxia, as well as pharmacological study of drug. Successful accomplishment of the goals of this project will enhance our understanding of clinical glioblastoma and lay the foundation for future novel clinical treatment regimens towards chemotherapy in combination with radiotherapy. PUBLIC HEALTH RELEVANCE: Glioblastoma multiform (GBM) is the most common and lethal intracranial cancer, and highly resists to conventional multimodal therapies. These tumors are characterized by profound angiogenesis, disrupted blood-brain-barrier, vasogenic edema, as well as regions of hypoxia and necrosis, which have been shown to correlate negatively with clinical outcome. We propose to apply bioluminescent imaging (BLI), based on a hypoxia reporter gene, and a novel MRI approach to assessing dynamic change of intra-tumor hypoxia and vascular characteristics in orthotopic GBM models, and to further understand pathophysiological mechanisms underlying the clinical benefits from antiangiogenic agents such as bevacizumab.

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是最常见和最致命的颅内癌症，对传统的多模式治疗具有高度的抵抗力。这些肿瘤的特点是严重的血管生成，血脑屏障(BBB)被破坏，血管源性水肿，以及缺氧和坏死区，已被证明与局部肿瘤控制，无病生存和总体生存呈负相关。有相当多的轶事证据表明，肿瘤内缺氧可以增强辐射抵抗力。然而，在缺乏可靠的监测方法的情况下，在活体内，肿瘤内的动态氧气状态仍未在GBM中得到检验。我们已经开发了一种使用生物发光报告系统来监测肿瘤内缺氧的遗传策略。通过将低氧诱导因子1a-萤火虫荧光素酶(HIF-1a-ODD-LUC)导入多种GBM细胞，包括从患者新鲜的GBM肿瘤中分离出来的细胞表面标志物CD133，我们将能够通过生物发光成像(BLI)实时监测原位GBM模型中肿瘤的缺氧情况。我们还建议开发基于交错T2(BOLD，血氧水平依赖)和T1(组织氧水平依赖)加权序列的MRI技术，用于评估原位GBM模型中的肿瘤氧合，包括基线缺氧、空间异质性和干预反应的动力学。此外，还将通过动态磁化率对比(DSC)和动态对比增强(DCE)MRI来评估血管灌注、血脑屏障状态与缺氧的相关性。最近有报道称，在使用抗血管生成药物和化疗药物辅助治疗后，GBM患者的总体生存率和无进展生存率都有所提高。然而，潜在的机制仍不清楚。我们推测，体内肿瘤缺氧和血管生成的多模式成像将增强我们对有效抗血管生成的病理生理机制的理解，并进一步促进放化疗组合的优化。该项目的主要目标是整合通过多模式成像获得的肿瘤缺氧和血管形成的多个参数，以与肿瘤侵袭性相关，并了解抗血管生成治疗临床益处的病理生理机制。成像结果将与组织学和免疫组织化学研究的灌注、血管密度和低氧，以及药物的药理学研究相关联。本项目目标的顺利完成将提高我们对胶质母细胞瘤临床的认识，并为未来化疗结合放射治疗的新的临床治疗方案奠定基础。 公共卫生相关性：多形性胶质母细胞瘤(GBM)是最常见和最致命的颅内癌症，对传统的多模式治疗具有高度抵抗力。这些肿瘤的特点是严重的血管生成，血脑屏障破坏，血管源性水肿，以及缺氧区和坏死区，这些已被证明与临床结果呈负相关。我们建议应用基于缺氧报告基因的生物发光成像(BLI)和一种新的MRI方法来评估原位GBM模型中肿瘤内缺氧和血管特征的动态变化，并进一步了解贝伐单抗等抗血管生成药物临床益处的病理生理机制。