基于功能和分子MRI的贝伐单抗治疗胶质母细胞瘤的作用机制研究

Glioblastoma is the most common primary intracranial tumors in adults, and patients with glioblastoma remains universally fatal with a median survival of 12-15 months. In recent years, the application of anti-angiogenic drugs has provided a new strategy for the treatment of glioblastoma. Bevacizumab, a kind of monoclonal antibody, is the first approved anti-angiogenic drug in the world, but so far, the mechanism and efficacy of Bevacizumab to recurrent glioblastoma is still unknown, which has become the current research focus. The development of functional and molecular MRIs makes it possible to investigate the mechanism of drugs in vivo at the molecular level. Arterial spin labeling (ASL) and susceptibility-weighted imaging (SWI) can be used to non-invasively evaluate the tumor perfusion and vascular density. Amide proton transfer (APT) is a new emerging MRI technique which can noninvasively detect endogenous proteins and peptides in the tumor tissue at molecular level. In this study, noninvasive techniques including ASL, SWI, and APT will be used to quantitatively evaluate the response of microvasculature and microenvironment in recurrent glioblastoma to Bevacizumab therapy. The changes of molecular biomarkers (VEGF、VEGFR2、MMP-2、TIMP-2、SDF1α、PLGF and bFGF) in the blood will also be detected. Then the association between imaging biomarkers, molecular biomarkers, the tumor response and survival time of patients will be analyzed, respectively. If the project is successful, the results will provide direct evidence in vivo for the mechanism of bevacizumab and imaging and circulating biomarkers for the earlier prediction of therapeutic efficacy of glioblastoma to anti-angiogenic treatment, thus promoting the development of molecular targeted therapy.

胶质母细胞瘤是成人最常见和死亡率最高的颅内原发肿瘤，近年来抗血管生成药的应用为胶质母细胞瘤的治疗提供了新策略。贝伐单抗是全球首个被批准使用的抑制血管生成的药物，但迄今为止，贝伐单抗治疗胶质母细胞瘤的作用机制及其效果尚不确定，为当前研究的热点。近年来，功能和分子MRI技术的发展，为从分子水平在体探讨药物作用机制提供了可能。本研究拟采用无创性动脉血质子自旋标记（ASL）、磁敏感加权成像（SWI）和基于内源性蛋白质的分子MRI新技术氨基质子转移（APT）MRI，定量评价贝伐单抗治疗复发性胶质母细胞瘤中肿瘤微血管和微环境的变化，同时检测血液中多个分子生物学指标（包括VEGF、VEGFR2、SDF1α、PLGF和bFGF等）的变化，与肿瘤治疗反应及患者生存时间相结合，为明确贝伐单抗的作用机理提供直接的在体证据，为早期预测胶质母细胞瘤抗血管生成疗效提供影像学和循环生物标志物，促进分子靶向治疗的发展。

脑胶质瘤是成人最常见的颅内原发性肿瘤，不同级别脑胶质瘤的治疗方案不同。因此，脑胶质瘤的准确分级对于临床治疗方案的选择至关重要。本项目采用包括多种模型的磁共振扩散加权成像（diffusion-weighted imaging, DWI）、扩散峰度成像（diffusion kurtosis imaging, DKI）、酰胺质子转移（amide proton transfer, APT）成像和三维伪连续性动脉血质子自旋标记（pseudo-continuous arterial spin labeling, pCASL）成像在内的无创性多模态磁共振成像技术，为提高脑胶质瘤分级准确性和评价胶质母细胞瘤贝伐单抗治疗过程中肿瘤微血管和微环境的变化展开研究。我们目前的研究结果显示，与常规的磁共振扩散成像参数相比，拉伸指数模型DWI生成的反映组织异质性参数α和DKI生成的反映组织复杂程度参数平均峰度（mean kurtosis，MK）不仅能够提高脑胶质瘤分级的准确性，而且可以提供更多的信息。另外，我们发现APT磁共振成像与常规DWI和pCASL成像技术相比，能够提高脑胶质瘤分级的准确性并可以更加准确地反映脑胶质瘤的细胞密度。这些研究结果对于脑胶质瘤患者治疗方案的选择及预后评估有着重大临床意义，不仅为提高脑胶质瘤的准确分级提供了新的无创性工具，而且为早期预测胶质瘤疗效提供了无创性影像学生物标记物。