文章：

目标转移

Targeting metastasis

原文发布日期：2016-03-24

DOI: 10.1038/nrc.2016.25

类型: Review Article

开放获取: 否

要点：

1. Metastases, and complications of their treatment, are significant causes of patient morbidity and mortality. Drugging metastasis pathways represents a potential new therapeutic opportunity.
2. Most preclinical experiments demonstrate partial prevention of metastasis rather than shrinkage of existing lesions. These data would apply to the prevention of an initial metastasis in a high-risk patient, or the prevention of additional metastases in patients with treated, limited metastatic disease.
3. Metastatic colonization represents the best 'open' therapeutic window in metastasis. It is the progressive outgrowth of tumour cells in a distant location, influenced by tumour cell signalling and interaction with a modified microenvironment (the formation of a premetastatic niche, alterations in the extracellular matrix and stromal cells, innate and T cell immunity and altered vascular supply).
4. Denosumab, a monoclonal antibody that blocks the receptor activator of NF-κB ligand (RANKL; which is involved in the bone metastatic process), provides evidence that metastasis can be successfully drugged. Denosumab clinical trials used an interesting primary end point — skeletal-related events (SREs).
5. The development of metastasis prevention agents may be hindered by their cytostatic nature, which will not result in shrinkage of established metastatic lesions (responses) in early clinical testing. New clinical trial designs for primary and secondary metastasis prevention are needed to lower the time, cost and cohort sizes of traditional adjuvant trials.
6. It is likely that a single metastasis-preventive agent will not be maximally effective. As for HIV, a combination of distinct classes of drugs, given early and continuously, will be key.

要点翻译：

1. 转移灶及其治疗引起的并发症是导致患者发病和死亡的重要原因。针对转移通路进行药物治疗代表了一种潜在的新治疗机遇。
2. 多数临床前实验表明，这些治疗能部分预防转移发生，而非使现有转移灶缩小。这些数据适用于高危患者初次转移的预防，或已治疗且转移灶有限的患者新增转移的预防。
3. 转移性定植是转移过程中最佳的"开放"治疗窗口。这是肿瘤细胞在远处部位的渐进性生长，受到肿瘤细胞信号传导与修饰微环境相互作用的影响（包括转移前微生态的形成、细胞外基质与基质细胞的改变、先天性与T细胞免疫以及血管供应的变化）。
4. 地诺单抗是一种阻断NF-κB配体受体激活剂（RANKL，参与骨转移过程）的单克隆抗体，其疗效证实转移灶可以被成功药物干预。地诺单抗临床试验采用了一个有趣的主要终点——骨骼相关事件（SREs）。
5. 转移预防药物的研发可能因其细胞抑制特性而受阻，这在早期临床测试中不会导致已形成转移灶的缩小（应答）。需要建立针对原发性和继发性转移预防的新临床试验设计，以缩短传统辅助试验的时间、降低成本和减少队列规模。
6. 单一转移预防药物很可能无法实现最大疗效。如同HIV治疗，早期持续联合使用不同类别的药物将是关键所在。

英文摘要：

Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined.

摘要翻译： 

肿瘤转移，即肿瘤细胞从原发部位播散并相继定植于远隔器官，是癌症患者死亡的主要原因。治疗目标包括：在高危患者中预防初次转移，对已形成的病灶进行缩小，以及在病变有限的患者中防止进一步转移。肿瘤细胞并非自主行动，而是与转移微环境进行双向互动，从而改变抗肿瘤免疫、细胞外环境、基因组稳定性、存活信号、化疗耐药性及增殖周期。针对这些相互作用能否显著改善患者预后？本综述重新审视了临床前研究、联合疗法及临床试验设计。

原文链接：

Targeting metastasis