MRI Monitoring of Angiogenesis Inhibition

描述（由申请人提供）： 该项目的总体目标是开发动态MRI方法，使用大分子造影剂（MMCM）增强，用于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一起使用，以估计分数血容量（fBV），作为血管分布的衡量标准，以及内皮转移系数（KPS），作为肿瘤血管渗漏的衡量标准。总体假设是血管生成抑制剂改变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检测和定量。该方法利用了肿瘤血管中大量大分子的泄漏。计划的研究将确定MR/测量值是否可以作为肿瘤血管生成的生物标志物，并且在治疗过程的早期使用时，可以预测对抗血管生成治疗的长期反应。我们计划的研究将确定MRI方法在评估血管生成抑制剂中的效用，这些抑制剂通过血管内皮生长因子（VEGF）和其他与血管生成有关的元素起作用。他们还将阐明抗血管生成药物对细胞毒性药物向肿瘤细胞输送的影响。补充荧光，共聚焦，和电子显微镜研究，重点是血管生成抑制剂诱导的内皮细胞，周细胞和肿瘤血管的基底膜的变化，将提供洞察的MRI方法评估的血管功能的细胞变化。MRI方法应有助于在临床前模型中筛选血管生成抑制剂，应加强抗血管生成药物临床试验的设计-包括使用血管生成抑制剂和细胞毒性药物组合的试验，并最终应改善对癌症患者抗血管生成治疗的临床反应评估。

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.