MRI Contrast Agent Methods of Assessing Tumor Angiogenesis

描述(申请人提供)：脑瘤患者迫切需要新的治疗方法。最近的临床研究表明，将抗血管生成药物与传统疗法相结合，患者的反应有了显著的改善，导致了FDA批准的第一批抗血管生成药物。然而，为了充分实现联合治疗的前景，我们需要非侵入性方法来回答这些药物如何发挥作用以及如何以最佳方式结合的关键问题。因此，本研究的总体目标是开发和验证动态磁化率对比(DSC)MRI方法来监测肿瘤血管生成和血管正常化，这是非常相关和及时的。我们已经确定了肿瘤中基于易感性的生物物理关系，并开发了GE-SE(梯度回波/自旋回波)方法，结合对比泄漏校正，提供总(GE)和微血管(SE)脑血容量(CBV)、平均血管直径(MVD)、脑血流量(CBF)和平均通过时间(MTT)的测量。我们已经证明这些与肿瘤分级相关，指导术中诊断，并区分放射效应和肿瘤复发。我们在大鼠脑肿瘤中显示了抗血管生成治疗的剂量依赖性反应，以及提示血管正常化的效果，这可能解释了联合治疗的成功。具体目标是这项工作合乎逻辑和令人兴奋的延伸。我们将继续表征和验证敏感性造影剂方法的准确性。通过比较MRI和显微镜测量大鼠脑肿瘤模型和II的CBV和MVD。通过使用我们开发的一种新的肿瘤特异性DSC模拟模型(目标1)。DSC方法识别血管正常化的能力，从而优化治疗时机的能力，将通过动物联合抗血管生成和放射治疗研究来确定(目标2)。将经泄漏校正的GE/SE结果翻译给更广泛的科学和临床受众需要将我们的方法与其他获取和分析方法进行比较(目标3)。最后，将在患者身上测试多参数DSC方法预测存活率和跟踪抗血管生成治疗反应的有效性(目标4)。因此，这项研究的完成将改进DSC方法在评估肿瘤血管生成和联合治疗策略方面的应用和解释，从而最终将其纳入常规临床实践，造福于脑肿瘤患者。

DESCRIPTION (provided by applicant): Patients with brain tumors are in desperate need of new therapies. Recent clinical studies combining anti- angiogenic agents with conventional therapies have shown significant improvements in patient response leading to the first FDA-approved anti-angiogenic agents. Yet, to fully realize the promise of combined therapies, we need non-invasive methods that can answer critical questions about how these agents work and how to combine them optimally. Thus, the overall goal of this research, which is to develop and validate DSC (dynamic susceptibility contrast) MRI methods to monitor tumor angiogenesis and vascular normalization, is quite relevant and timely. We have characterized susceptibility-based biophysical relationships in tumors and developed a GE-SE (gradient-echo/spin-echo) method, with contrast-leakage correction, to provide measures of total (GE) and microvascular (SE) cerebral blood volume (CBV), mean vessel diameter (mVD) cerebral blood flow (CBF), and mean transit time (MTT). We have shown these to correlate with tumor grade, guide intraoperative diagnosis and distinguish radiation effects from tumor recurrence. We demonstrated a dose-dependent response to anti-angiogenic therapy in rat brain tumors, and an effect suggestive of vascular normalization, which may explain the success of combined therapies. The specific aims are logical and exciting extensions of this work. We will continue to characterize and validate the accuracy of susceptibility contrast agent methods i. by comparing MRI and microscopy measures of CBV and mVD in rat brain tumor models and ii. by using a novel tumor-specific DSC simulation model developed by us (Aim 1). The ability of DSC methods to identify vascular normalization, and thus optimize treatment timing, will be determined with combined anti-angiogenic and radiation therapy studies in animals (Aim 2). Translation of the leakage-corrected GE/SE results to a wider scientific and clinical audience requires the comparison of our approach to other acquisition and analysis methods (Aim 3). Finally, the utility of multiparameter DSC methods to predict survival and track response to anti-angiogenic therapies will be tested in patients (Aim 4). Thus, completion of this study should improve the application and interpretation of DSC methods for the evaluation of tumor angiogenesis and combined therapeutic strategies so that it will ultimately be accepted into routine clinical practice for the benefit of brain tumor patients.