MRI Assessment of Anti-angiogenesis in Mouse Gliomas

描述(申请人提供)：恶性胶质瘤是血管最好的肿瘤之一，包括多形性胶质母细胞瘤(GBM)，其预后仍然非常差，需要新的治疗方法。围绕多形性胶质母细胞瘤(GBM)诊断的死亡率可部分归因于与该肿瘤相关的强大的血管生成。血管生成是肿瘤进展的重要组成部分，有效的抗血管生成化合物可能提供特别的希望。根据定义，血管生成过程涉及肿瘤和宿主之间的相互作用，因此最终必须在体内模型中进行评估。具体目标1是开发和调整灌注MRI方法，以非侵入性评估恶性胶质瘤小鼠颅内模型中血管的演变变化。高场显微成像技术将被用来获得与血流、血容量和血管通透性相关的关键灌注参数的高分辨率、纵向和全面的评估。将采用基于T2*的动态磁化率对比磁共振成像(DSC-MRI)测量脑血流量和体积。这将采用一种新的方法，使用超顺磁性氧化铁造影剂Feridex，以最大限度地减少血管外渗。还将采用基于T1的动态增强磁共振成像(DCE-MRI)方法来测量造影剂体积转移常数KTrans。Ktras是血管通透性的指标，也是肿瘤新生血管的重要标志，即血脑屏障的破坏。这也将利用新的方法，通过应用大分子造影剂P792。提出了在同一成像会话中实施这些诊断方法的策略。这两种方法提供的灌注参数将提供关键的和互补的血管信息。结合解剖MRI成像方法，该项目的特定目标2将展示这些方法在评估三(3)种生物学上不同的抗血管策略对小鼠脑胶质瘤的效果的实用性。这些实验将结合免疫组织学方法和平均血管密度的量化来实施，目的是与灌注MRI结果进行比较。该项目将首次在小鼠胶质瘤模型中获得抗血管生成/抗血管效应的非侵入性文献，重要的是，将为在小鼠恶性胶质瘤模型中进行非侵入性、纵向和高度诊断性的抗血管策略研究奠定基础。最常见的起源于大脑的肿瘤是多形性胶质母细胞瘤(GBM)。GBM的预后仍然非常差，部分原因是这种肿瘤具有积极发展支持性血管网络(血管系统)的能力。这项建议将使用新的MRI策略来获得对小鼠GBM模型中肿瘤血管的高分辨率、非侵入性评估，该评估可用于评估针对该血管网络的GBM的治疗。

DESCRIPTION (provided by applicant): Malignant gliomas are among the best-vascularized tumors and include glioblastoma multiforme (GBM), for which prognosis remains extremely poor and for which novel therapeutic modalities are required. The mortality surrounding the diagnosis of glioblastoma multiforme (GBM) can be attributed in part to the robust angiogenesis associated with this tumor. Angiogenesis is an essential component of tumor progression, and effective anti-angiogenic compounds, may offer particular promise. By definition, the angiogenic process involves interaction between tumor and host, and hence ultimately must be evaluated in in vivo models. Specific Aim 1 is to develop and adapt perfusion MRI methodologies for the purpose of noninvasive evaluation of the evolving vasculature changes within mouse intracranial models of malignant glioma. High field micro-imaging technology will be employed to obtain a high resolution, longitudinal, and comprehensive assessment of the critical perfusion parameters relating to blood flow, blood volume and vascular permeability. T2* based dynamic susceptibility contrast MRI (DSC-MRI) will be employed to measure cerebral blood flow and volume. This will employ a novel approach, using a superparamagnetic iron oxide contrast agent, Feridex, to minimize extravascular extravasation. The T1 based dynamic contrast enhanced MRI (DCE-MRI) approach will also be implemented to measure Ktrans, the contrast agent volume transfer constant. Ktrans is an index of vascular permeability, and an important marker of tumor neovasculature, the disruption of the blood brain barrier. This will also utilize novel methodology, via application of the macromolecular contrast agent P792. Strategies for implementing these diagnostic methodologies in the same imaging session are proposed. The perfusion parameters provided by these two approaches will provide critical and complementary vascular information. In combination with anatomical MRI imaging approaches, Specific Aim 2 of the project will then demonstrate the utility of these methodologies in assessing the effect of three (3) biologically distinct anti-vascular strategies on mouse glioma. The experiments will be implemented in conjunction with immunohistologic approaches, and quantification of mean vessel density, for the purpose of comparison to the perfusion MRI results. The project will obtain the first non-invasive documentation of an anti-angiogenic/anti-vascular effect in a mouse glioma model, and importantly, will lay the groundwork for noninvasive, longitudinal and highly diagnostic investigations of anti-vascular strategies in mouse models of malignant glioma. The most common of the tumors which originate in the brain is glioblastoma multiforme (GBM). Prognosis for GBM remains extremely poor, in part because of this tumor's ability to aggressively develop a supportive blood vessel network (vasculature). This proposal will employ novel MRI strategies to obtain a high resolution, noninvasive assessment of tumor vasculature in mouse models of GBM, which can be used to evaluate treatments for GBM which target this vascular network.