全脑放疗联合EGFR-TKIs的时序对神经认知功能的影响及其潜在机制

Brain metastases is the common complication for EGFR-mutated NSCLC. EGFR-TKIs and whole brain radiotherapy (WBRT) are the most used treatments for those patients. However, until now, it is not clear which is the optimal sequence of the combination therapy of EGFR-TKIs and WBRT (early or late). Cognition impairment is one of the main late complications and dose-limiting toxicities for WBRT. Some researches, including previous retrospective study from our research team, indicated the combined therapy might increase the incidence of cognition impairment. The proliferation of astrocytes and microglial cells in hippocampus induced by radiotherapy, and the neuroinflammation caused by sequential inflammatory cytokines releasing are the one of the major cause for cognition impairment. The previous in vivo study, completed by our research team, indicated EGFR-TKI could induce hippocampus astrocytes proliferation. The phase I study, which completed by our research team, indicated the intracranial efficacy of EGFR-TKI had some correlation with its blood-brain barrier (BBB) permeability. The third generation of EGFR-TKI had a high BBB permeability and a satisfactory intracranial efficacy, however, its potential toxicity to the brain because of the high BBB permeability should also be concerned. In this study, we try to determine the exact mechanism of cognition impairment caused by the combined treatment of EGFR-TKI and WBRT.

多发肿瘤脑转移是EGFR突变阳性非小细胞肺癌的常见并发症。EGFR-TKIs及全脑放疗（WBRT）是其常用的治疗方式，但两者最佳的联合时序（早/晚WBRT）目前还存在着较大争议。神经认知功能损伤是WBRT的主要晚期并发症及剂量限制性毒性。本团队的前期研究显示脑部放疗联合EGFR-TKIs增加了神经认知功能损伤的发生率。放疗诱发海马区星形胶质细胞和小胶质细胞增殖，抑制神经发生，产生炎性因子导致神经炎症，是放疗导致神经认知功能损伤的重要原因。本团队的前期研究显示EGFR-TKI也可诱发大鼠海马区星形胶质细胞增多,有导致神经认知功能障碍的可能。本团队前期完成的I期临床研究显示EGFR-TKI的血脑屏障通透率同其颅内疗效有一定的相关性，但疗效的提高是否同时导致神经系统毒性的增加，也应加以关注。本研究旨在明确EGFR-TKIs联合早或晚WBRT，及其血脑屏障通透率对神经认知功能的影响及其潜在机制。

脑转移是表皮生长因子受体（Epidermal Growth Factor Receptor, EGFR）突变阳性非小细胞肺癌的常见并发症。表皮生长因子受体酪氨酸激酶抑制剂（Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, EGFR-TKIs）及大分割立体定向放疗（Hypofractionated Stereotactic Radiotherapy, HSRT）是其常见的治疗方式。EGFR-TKI的血脑屏障通透率同其颅内疗效有一定的相关性，但提高EGFR-TKI的脑脊液浓度可能产生神经认知方面的毒副作用。因此，本研究主要内容以提高血脑屏障通透率为出发点，建立斑马鱼颅内移植瘤模型，并利用斑马鱼颅内移植瘤模型筛选到notch抑制剂能特异的打开微小脑肿瘤的血脑屏障，并促进联用药物进入脑实质将药物靶向投递至肿瘤位置，从而达到减少药物脑脊液浓度的同时提高肿瘤内药物累积的效果。这对于在低毒副作用的前提下提升颅内肿瘤的治疗效果具有很好的临床应用前景。此外，本研究应用功能成像技术证实EGFR-TKIs可造成脑组织结构改变，明确其对认知功能毒副反应的结构基础；明确了热塑头肩模架实现HSRT所要求体位固定精度的相应条件，明确了基于部分病灶容积旋转调强（Partial Metastases-Volumetric Modulated Arc Therapy, PM-VMAT）技术及固定铅门VMAT（Fixed Jaw- Volumetric Modulated Arc Therapy, FJ-VMAT）技术的HSRT，可在保证靶区剂量覆盖的基础上减少正常脑转移的受照剂量，明确了EGFR-TKIs联合巩固性HSRT可能为EGFR突变阳性NSCLC脑转移患者的合理治疗方式。以上内容通过药物对脑转移肿瘤的靶向投递，进一步提高肿瘤脑转移临床疗效提供了实验基础，建立了研究平台，有明确的应用前景；同时优化了联合治疗细节，在提高疗效的同时减少了中枢神经系统毒副反应。

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