MR assessment of antiangiogenic therapy

描述：(申请人提供) 现在有相当多的证据表明动态造影剂增强 磁共振成像(MRI)数据，当使用适当的 药代动力学模型，能够提供有关 血管体积分数(FVV)、通透性表面积乘积(PS)、 肿瘤的造影剂反流率(KR)。如果被证明是准确的，如 非侵入性测量将在评估药物治疗效果方面发挥重要作用 抗血管生成治疗及其在预测化疗药物疗效中的作用 会通过扩散和对流过程渗透到肿瘤中。 到目前为止，已经进行的研究有限，而且往往相互矛盾。 磁共振活体测量的FVV、PS和KR与现有“金”的相关性 标准“，如基于免疫组织化学的微血管密度测量 和血管通透性。此外，严格比较磁共振成像得出的 使用FDA批准的低分子造影剂和 使用理论上具有优势的高分子量介质获得的 目前正在进行的临床试验有限。需要这样的研究来确定 使用每类造影剂评估FVV、PS、 和KR。这些问题必须在应用之前解决 无创方法在临床疗效监测中的应用前景 抗血管生成治疗。这个项目的总体目标是1) 证明准确的FVV、PS和KR的体内定量测量可以 通过单和/或双示踪剂药代动力学模型获得 造影剂增强的MRI数据，以及2)在这两种情况下的相关测量 动物模型和人类研究，以及其他血管生成的替代标记物， 包括特定血管生成因子、蛋白水解酶的表达， 内皮细胞凋亡和内皮细胞特异性标记物。这个 本项目的具体目标是：1)单、双示踪剂的关联 高、中、低剂量组的FVV、PS和KR的药代动力学测量 免疫组织化学和放射性核素低分子造影剂 微血管密度和血管通透性测定；2) FVV、PS和KR在人体内的纵向药代动力学研究 经抗血管生成治疗的皮下移植瘤，以及 这些指标与血管生成和血管生成的其他替代标志物的相关性 血管通透性；3)获得纵向药动学 参加抗血管生成药物临床试验的患者的措施，以及 这些指标与其他侵袭性替代标记物的相关性 血管生成。

Description: (provided by applicant) There is now considerable evidence that dynamic contrast agent-enhanced magnetic resonance imaging (MRI) data, when analyzed with appropriate pharmacokinetic models, are able to provide quantitative information regarding the vascular volume fraction (fvv), permeability-surface area product (PS), and contrast agent reflux rate (kR) in tumors. If shown to be accurate, such non-invasive measures will be highly useful in evaluating the efficacy of antiangiogenic therapies and in predicting how well chemotherapeutic agents will penetrate into tumors through diffusive and convective processes. Limited, and often contradictory, studies have been performed to date to correlate MRI-derived in vivo measures of fvv, PS, and kR with existing "gold standards" such as immunohistochemistry-based measures of microvessel density and vascular permeability. Furthermore, rigorous comparisons of MRI-derived measures obtained using FDA-approved low molecular weight contrast media with those obtained using theoretically advantageous higher molecular weight media currently in clinical trials are limited. Such studies are needed to establish the limitations of using each class of contrast media in assessing fvv, PS, and kR. These issues must be resolved prior to the application of such promising non-invasive measures to clinical monitoring of the efficacy of antiangiogenic therapy. The overall goals of this project are to 1) demonstrate that accurate in vivo quantitative measures of fvv, PS, and kR can be obtained via single and/or dual tracer pharmacokinetic modeling of dynamic contrast agent-enhanced MRI data, and 2) correlate such measures, in both animal models and human studies, with other surrogate markers of angiogenesis, including expression of specific angiogenic factors, proteases, rates of endothelial cell apoptosis, and endothelial cell-specific markers. The specific aims in this project are: 1) correlation of single and dual tracer pharmacokinetic measures of fvv, PS, and kR obtained using high, medium, and low molecular weight contrast agents with immunohistochemical and radionuclide determinations of microvessel density and vascular permeability; 2) acquisition of longitudinal pharmacokinetic measures of fvv, PS, and kR in subcutaneously implanted tumors treated with antiangiogenic therapies, and correlation of these measures with other surrogate markers of angiogenesis and vascular permeability; and 3) acquisition of longitudinal pharmacokinetic measures in patients enrolled in clinical trials of antiangiogenic drugs, and correlation of these measures with other invasive surrogate markers of angiogenesis.