MRI Monitoring of Angiogenesis Inhibition

描述(由申请人提供)： 该项目的总体目标是开发使用大分子造影剂(MMCM)增强的动态MRI方法，以监测肿瘤对血管生成抑制剂的反应。我们以前的研究表明，MMCM可以与MRI一起用来估计分数血容量(FBV)，作为衡量血管的指标，以及内皮转移系数(KPS)，作为衡量肿瘤血管泄漏的指标。总体假设是，血管生成抑制剂改变了肿瘤血管的结构和功能，包括它们对大分子溶质的泄漏，其方式可以通过动态MRI检测和量化。该方法利用了众所周知的肿瘤血管大分子泄漏的优势。计划中的研究将确定MR/测量是否可以作为肿瘤血管生成的生物标记物，当在治疗过程的早期使用时，可以预测抗血管生成治疗的长期反应。我们计划的研究将确定MRI方法在评估通过血管内皮生长因子(VEGF)和其他与血管生成有关的元素发挥作用的血管生成抑制剂方面的效用。他们还将阐明抗血管生成药物对向肿瘤细胞输送细胞毒剂的影响。互补荧光、共聚焦和电子显微镜研究，重点是血管生成抑制剂诱导的血管内皮细胞、周细胞和基底膜的变化，将深入了解MRI方法评估的血管功能潜在的细胞变化。MRI方法应该有助于在临床前模型中筛选血管生成抑制剂，应该加强抗血管生成药物的临床试验的设计--包括使用血管生成抑制剂和细胞毒性药物的联合试验，并最终应该改善对癌症患者抗血管生成治疗的临床反应的评估。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop dynamic MRI methods, using macromolecular contrast media (MMCM) enhancement, for monitoring the response of tumors to inhibitors of angiogenesis. Our previous studies have shown that MMCM can be used with MRI to estimate fractional blood volume (fBV), as a measure of vascularity, and the endothelial transfer coefficient (KPS), as a measure of tumor vascular leakiness. The overall hypothesis is that inhibitors of angiogenesis alter the structure and function of tumor blood vessels, including their leakiness to macromolecular solutes, in ways that can be detected and quantified by dynamic MRI. The approach takes advantage of the well-documented macromolecular leakiness of tumor blood vessels. Planned studies will determine if the MR/measurements can serve as biomarkers of tumor angiogenesis and, when used early in the course of treatment, can predict the long-term response to antiangiogenic therapy. Our planned studies will determine the utility of the MRI methods in assessing angiogenesis inhibitors that act through vascular endothelial growth factor (VEGF) and other elements implicated in angiogenesis. They will also elucidate the effect of antiangiogenic drugs on the delivery of cytotoxic agents to tumor cells. Complementary fluorescence, confocal, and electron microscopic studies, with a focus on changes induced in endothelial cells, pericytes, and basement membranes of tumor vessels by angiogenesis inhibitors, will give insight into cellular changes underlying vascular functions assessed by the MRI methods. The MRI methods should facilitate the screening of angiogenesis inhibitors in preclinical models, should strengthen the design of clinical trials of antiangiogenic drugs - including trials using combinations of angiogenesis inhibitors and cytotoxic drugs, and ultimately should improve assessment of clinical responses to antiangiogenic therapies in cancer patients.