MRI Contrast Agent Methods of Assessing Tumor Angiogenesis

描述（申请人提供）：脑肿瘤患者迫切需要新的治疗方法。最近的临床研究将抗血管生成药物与常规疗法相结合，显示出患者反应的显著改善，这导致了fda批准的第一个抗血管生成药物。然而，为了充分实现联合治疗的前景，我们需要非侵入性的方法来回答这些药物如何起作用以及如何最佳地结合它们的关键问题。因此，本研究的总体目标是开发和验证DSC（动态敏感性对比）MRI方法监测肿瘤血管生成和血管正常化，这是非常有意义和及时的。我们描述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，并进行了对比泄漏校正，以提供总（GE）和微血管（SE）脑血容量（CBV），平均血管直径（mVD）脑血流量（CBF）和平均传递时间（MTT）的测量。我们已经证明这些与肿瘤分级相关，指导术中诊断和区分放射效应与肿瘤复发。我们在大鼠脑肿瘤中证明了抗血管生成治疗的剂量依赖性反应，以及血管正常化的效应，这可能解释了联合治疗的成功。具体目标是这项工作的逻辑和令人兴奋的扩展。我们将继续表征和验证敏感性对比剂方法的准确性：1 .通过比较大鼠脑肿瘤模型中CBV和mVD的MRI和显微镜测量；使用我们开发的一种新的肿瘤特异性DSC模拟模型（Aim 1）。DSC方法识别血管正常化的能力，从而优化治疗时机，将通过动物抗血管生成和放射治疗联合研究来确定（目的2）。将泄漏校正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，将在患者中测试多参数DSC方法预测生存和跟踪抗血管生成治疗反应的效用（目标4）。因此，本研究的完成将提高DSC方法在肿瘤血管生成评估和联合治疗策略中的应用和解释，最终将其纳入常规临床实践，造福脑肿瘤患者。

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.