文章：

脑转移作为预防和治疗的靶点

Brain metastases as preventive and therapeutic targets

原文发布日期：2011-04-07

DOI: 10.1038/nrc3053

类型: Review Article

开放获取: 否

要点：

1. Brain metastases are most common in patients with lung cancers, breast cancers or melanoma.
2. Treatment includes surgery and radiation therapy. Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline.
3. In animal models of brain metastasis, tumour cells crawl outside the blood vessels and interact with an inflamed neural microenvironment to colonize the brain.
4. Alterations in the expression of several genes, including ERBB2, ST6GALNAC5, TCF, transforming growth factor-β (TGFB), vascular endothelial growth factor (VEGF), Serpine1 and Timp1, have modulated brain metastasis.
5. Chemotherapeutic efficacy for brain metastases remains disappointing.
6. In experimental models, brain metastases opened the blood–brain barrier (BBB) several-fold over the normal brain, but only 10% of lesions exhibited sufficient drug permeability to mount an apoptotic response to chemotherapy.
7. BBB-permeable drugs are needed to improve chemotherapeutic efficacy.
8. Prevention of brain metastasis formation in mice has been observed in response to lapatinib, vorinostat, pazopanib, signal transducer and activator of transcription 3 (STAT3) inhibitors and VEGF receptor (VEGFR) inhibitors.
9. New trial designs could test drugs for the prevention of brain metastases. Secondary prevention trials would determine the time to the development of a new brain metastasis in patients with either one or several existing lesions.
10. Radiosensitizers may improve the efficacy of radiation therapy while sparing normal tissue.
11. Inhibition of the neuroinflammatory response is hypothesized to protect the brain from WBRT-induced cognitive decline.

要点翻译：

1. 脑转移最常见于肺癌、乳腺癌或黑色素瘤患者。
2. 治疗手段包括手术和放射治疗。全脑放疗已被证实可预防肺癌脑转移，但会导致认知功能下降。
3. 在脑转移动物模型中，肿瘤细胞爬出血管并与炎症性神经微环境相互作用实现脑部定植。
4. ERBB2、ST6GALNAC5、TCF、转化生长因子-β、血管内皮生长因子、丝氨酸蛋白酶抑制剂1及基质金属蛋白酶抑制剂1等多个基因的表达改变可调控脑转移进程。
5. 脑转移的化疗效果仍不理想。
6. 实验模型显示，脑转移灶使血脑屏障开放程度较正常脑组织增加数倍，但仅10%的病灶具有足够的药物渗透性以引发化疗凋亡反应。
7. 需要开发能透过血脑屏障的药物以提升化疗效果。
8. 在动物实验中观察到拉帕替尼、伏立诺他、帕唑帕尼、STAT3抑制剂及VEGFR抑制剂可预防脑转移形成。
9. 新型试验设计可测试预防脑转移的药物。二级预防试验将评估已存在单个或多个转移灶的患者出现新脑转移灶的时间。
10. 放射增敏剂可在保护正常组织的同时增强放疗效果。
11. 理论表明抑制神经炎症反应可保护大脑免受全脑放疗相关的认知功能损伤。

英文摘要：

The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood–tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology, to develop and implement new clinical trial designs. Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.

摘要翻译： 

脑转移瘤在癌症患者中的发病率明显上升，并可能抵消新型全身治疗所带来的获益。脑被视为“庇护所”，因为血-肿瘤屏障会限制药物进入并杀死肿瘤细胞。针对脑转移的转化研究必须是多学科的，将先进的化学、血-脑屏障药代动力学、神经认知测试和放射生物学与转移生物学结合起来，以开发和实施新的临床试验设计。本文还讨论了脑转移瘤化学预防的进展、肿瘤放射增敏剂的验证以及全脑放射治疗所致认知缺陷的改善。

原文链接：

Brain metastases as preventive and therapeutic targets