基于血管正常化时间窗优化胶质母细胞瘤抗血管生成治疗联合放化疗的研究

Glioblastoma (GBM) is the most common primary brain tumor in adults. Standard treatment median overall survival (OS) is only 14-15 months after diagnosis. Anti-angiogenic therapies were proposed an optimal approach for controlling GBM growth. However, recent research shows that the addition of bevacizumab for newly diagnosed GBM did not improve OS. Several preclinical and clinical studies indicate that anti-angiogenic therapy lead to vascular normalization. In the process of vascular normalization, the architecture of the remaining vasculature is largely restored, leading to reduced vessel permeability and thereby improving tumor blood flow and tumor oxygenation. The effects and duration the vascular normalization time window are no clear yet in GBM because of blood-brain barrier. Prior researches indicated that there is a dynamic change in tumor vascular morphology and function in tumor patients with glioblastoma after bevacizumab treatment. This study is designed to discover the change of tumor blood flow and oxygen supply after anti-angiogenic therapy with animal transplantation tumor and clinical research. We will explore the vascular normalization window and sensitization of tumor cells to radio-chemotherapy utilizing PET/CT molecular imaging and magnetic resonance functional imaging. Finally, an optimization method of anti-VEGF therapy combined with chemoradiotherapy can be built to improve response to treatment in patients with glioblastoma.

胶质母细胞瘤是最常见的原发性颅内恶性肿瘤，标准的术后放化疗疗效极差，合用贝伐珠单抗为代表的抗血管生成治疗成为研究热点，但临床疗效改善不显著。在肺癌等其他肿瘤中应用抗血管生成治疗会使肿瘤出现"血管正常化时间窗"，在该窗口期肿瘤血流灌注增加,氧供改善，联合放化疗可提高疗效。由于脑部位置的特殊性，胶质母细胞瘤"血管正常化时间窗"的出现及持续时间，以及该窗口期对于放化疗的意义均需要独立研究。前期研究发现，胶质母细胞瘤患者应用贝伐珠单抗治疗后，肿瘤血供和氧负荷存在动态变化。本课题拟通过人胶质母细胞瘤荷瘤裸鼠实验及患者的临床研究，应用PET/CT分子显像和磁共振功能影像确定抗血管生成治疗后的肿瘤血流灌注、氧供变化规律，确定其"血管正常化时间窗"，并探索该时间窗内的放化疗增敏作用，最终建立联合应用抗血管生成治疗、放疗、化疗的最优化方法，以提高胶质母细胞瘤治疗疗效。

按照任务书的要求，课题组成功建立胶质瘤原位癌模型，重点研究了PET /CT分子影像在监测抗血管生成治疗中的应用。我们应用18F-Alfatide这种新型新生血管示踪剂，主要进行了动物实验和临床试验两方面研究，从基础到临床，系统地研究并建立了应用PET/CT分子影像抗血管治疗疗效和副作用监测的模型。在动物实验水平，我们研究发现血管高密度肿瘤18F-alfatide PET显像值显著高于血管低密度的肿瘤，且血管高密度肿瘤抗血管生成治疗疗效显著好于肿瘤疗效。肿瘤18F-alfatide PET治疗基线水平与肿瘤短期抗血管生成治疗疗效显著相关（R2>0.5, P<0.05），肿瘤基线18F-alfatide PET与贝伐单抗联合化疗、放疗的疗效具有显著相关性（R2>0.5, P<0.05）。同时发现，抗血管生成治疗两周后小鼠脏器18F-alfatide PET显像显著低于对照组，且抗血管生成治疗组荷瘤鼠肝脏及肾脏HE染色的炎性细胞显著高于对照组，肝脏与肾脏的18F-alfatide PET摄取值与炎性细胞浸润情况呈显著相关，脏器基线18F-alfatide PET与小鼠抗血管生成治疗中脏器炎性细胞浸润程度显著相关。在临床方面，通过对胶质瘤病人研究发现，肿瘤病灶的摄取值越高，抗血管生成治疗的疗效越好，无进展生存时间越长。以肿瘤病灶SUVmean=3.82为阈值，发现18F-alfatide PET摄取值高对比摄取值低的客观缓解率分别是85.7％ vs. 22.9％，证实18F-alfatide PET/CT肿瘤血管生成显像可在基线水平预测抗血管生成靶向治疗敏感性。课题组首次将新型的血管生成显像用于无创性预测肿瘤抗血管生成治疗的疗效和毒副作用，建立了个体化抗血管生成靶向治疗疗效预测方法，成功验证了肿瘤中18F-alfatide PET摄取值与抗血管生成治疗疗效的相关性。