MRI Assessment of Anti-angiogenesis in Mouse Gliomas

描述（由申请人提供）：恶性胶质瘤是最好的血管化肿瘤之一，包括多形性胶质母细胞瘤（GBM），其预后非常差，需要新的治疗方式。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劲血管生成。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。具体目的1是发展和适应灌注MRI方法，以无创评估小鼠颅内恶性胶质瘤模型中血管变化的演变。采用高场微成像技术，对血流、血容量、血管通透性等关键灌注参数进行高分辨率、纵向、全面的评估。采用基于T2*的动态敏感性对比MRI （DSC-MRI）测量脑血流量和脑容量。这将采用一种新的方法，使用超顺磁性氧化铁造影剂，Feridex，以减少血管外渗。基于T1的动态对比增强MRI （DCE-MRI）方法也将用于测量造影剂体积传递常数Ktrans。Ktrans是血管通透性的指标，是肿瘤新生血管、血脑屏障破坏的重要标志。这也将利用新的方法，通过应用大分子造影剂P792。提出了在同一影像会议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和互补的血管信息。结合解剖MRI成像方法，该项目的Specific Aim 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胶质瘤的影响方面的效用。实验将与免疫组织学方法和平均血管密度的量化相结合，以便与灌注MRI结果进行比较。该项目将首次获得小鼠胶质瘤模型中抗血管生成/抗血管效应的非侵入性文献，重要的是，将为恶性胶质瘤小鼠模型中抗血管策略的非侵入性、纵向和高度诊断性研究奠定基础。最常见的肿瘤起源于大脑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（脉管系统）的能力。本研究将采用新颖的MRI策略，对GBM小鼠模型的肿瘤血管系统进行高分辨率、无创评估，可用于评估针对该血管网络的GBM治疗方法。

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.