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[黑色素瘤:从分子研究到治疗突破]

[Melanoma: from molecular studies to the treatment breakthrough].

作者信息

Imianitov E N

出版信息

Arkh Patol. 2013 Sep-Oct;75(5):63-72.

PMID:24341237
Abstract

Melanoma holds a leading position in the mortality from skin tumors. Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients. Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and, consequently, to the development of novel targeted drugs. More than a half of melanomas contain amine acid substitutions in serine-threonine kinase BRAF. Clinical trials involving specific BRAF inhibitors--vemurafenib and dabrafenib--demonstrated high efficacy of these agents towards BRAF-mutated melanoma. MEK inhibitors may show activity against both BRAF--and NRAS-driven tumors. Mucosal and acral melanomas frequently contain mutation in KIT receptor and can be successfully treated by imatinib. There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules CTLA4, PD-1 and PD-L1. In some instances these drugs allow to obtain exceptionally prolonged responses. Whole genome sequencing led to the identification of new melanoma genes, e.g. GRIN2A, TRRAP, PREX2, RAC1, STK19, PPP6C, etc. Molecular testing, especially BRAF mutation analysis, has become a mandatory part of melanoma diagnosis. Nevertheless, despite the revolution in melanoma treatment, the prevention of excessive ultraviolet exposure, cancer awareness and early diagnosis remain the main tools for the management of this disease.

摘要

黑色素瘤在皮肤肿瘤死亡率中占据主导地位。转移性黑色素瘤的标准治疗仅能使一小部分患者实现肿瘤缓解。对黑色素瘤分子发病机制的研究促使人们识别出了几种致病基因事件,进而推动了新型靶向药物的研发。超过半数的黑色素瘤在丝氨酸 - 苏氨酸激酶BRAF中存在氨基酸替代。涉及特异性BRAF抑制剂(维莫非尼和达拉非尼)的临床试验表明,这些药物对BRAF突变的黑色素瘤具有高效性。MEK抑制剂可能对BRAF和NRAS驱动的肿瘤均有活性。黏膜和肢端黑色素瘤常含有KIT受体突变,可通过伊马替尼成功治疗。还有针对免疫抑制分子CTLA4、PD - 1和PD - L1的新型治疗性单克隆抗体。在某些情况下,这些药物能带来异常持久的反应。全基因组测序促使人们识别出了新的黑色素瘤基因,如GRIN2A、TRRAP、PREX2、RAC1、STK19、PPP6C等。分子检测,尤其是BRAF突变分析,已成为黑色素瘤诊断的必要组成部分。然而,尽管黑色素瘤治疗取得了革命性进展,但预防过度紫外线暴露、提高癌症意识和早期诊断仍是管理该疾病的主要手段。

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