文章：

间皮瘤生物学的新见解及其治疗意义

Novel insights into mesothelioma biology and implications for therapy

原文发布日期：2017-07-25

DOI: 10.1038/nrc.2017.42

类型: Review Article

开放获取: 否

要点：

1. Malignant mesothelioma is a universally lethal cancer that usually affects the pleura, and it is increasing in incidence worldwide. Carcinogenesis in this disease is unique in that the direct causal relationship between exposure to the causative environmental carcinogen, asbestos, and the development of mesothelioma is so well established.
2. Currently, platinum–antifolate combination chemotherapy remains the only established treatment, with pemetrexed and cisplatin combination chemotherapy the only licensed regimen. Here, despite tumour response rates of 45.5%, as well as improvements in progression-free survival of 6.1 months, overall survival of 13.3 months and cancer-related symptoms, benefits are usually modest at best and prognosis remains poor, with population-level survival estimated at approximately 8 months, as many patients are unfit for active treatment.
3. There has been recent exponential growth in our understanding of mesothelioma pathobiology, with an improvement in our knowledge of mesothelioma genetics, epigenetics, tumour microenvironment and immunobiology. The translational outputs from these data have now led to the discovery and development of promising therapeutic strategies.
4. Extensive interrogation of the mesothelioma genome has revealed the most frequent mutational events to involve tumour suppressor inactivation, mediated by multiple mechanisms, which include single nucleotide variation, copy number losses, gene fusions and splicing alterations. Tumour suppressors commonly inactivated include those encoded by cyclin-dependent kinase inhibitor 2A (CDKN2A), BRCA1 associated protein 1 (BAP1) and neurofibromin 2 (NF2).
5. There are now several promising novel antitumour agents under investigation in mesothelioma, including mesothelin-targeted therapies, arginine deprivation in arginosuccinate synthetase 1-deficient mesothelioma and immunotherapeutics such as immune checkpoint inhibitors.

要点翻译：

1. 恶性间皮瘤是一种普遍致命的癌症，通常累及胸膜，且全球发病率持续上升。该疾病的致癌机制具有独特性，即暴露于环境致癌物石棉与间皮瘤发生之间的直接因果关系已得到明确证实。
2. 目前，铂类-抗叶酸联合化疗仍是唯一成熟的治疗方案，其中培美曲塞联合顺铂化疗是唯一获批的标准化疗方案。尽管该方案可实现45.5%的肿瘤缓解率，并将无进展生存期延长至6.1个月、总生存期延长至13.3个月，同时改善癌症相关症状，但疗效通常较为有限，预后仍然不佳。因众多患者无法耐受积极治疗，人群水平的总生存期仅约8个月。
3. 近年来我们对间皮瘤病理生物学的认知呈指数级增长，在遗传学、表观遗传学、肿瘤微环境和免疫生物学领域取得显著进展。基于这些研究成果的转化应用，现已推动具有潜力的治疗策略的发现与开发。
4. 对间皮瘤基因组的深度解析显示，最常见的突变事件涉及抑癌基因失活，其机制包括单核苷酸变异、拷贝数缺失、基因融合和剪接变异等。常见的失活抑癌基因包括细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）、BRCA1关联蛋白1（BAP1）和神经纤维蛋白2（NF2）编码的蛋白。
5. 目前有数种前景广阔的新型抗肿瘤药物正在间皮瘤领域开展研究，包括靶向间皮素疗法、针对精氨琥珀酸合成酶1缺陷型间皮瘤的精氨酸剥夺疗法，以及免疫检查点抑制剂等免疫治疗药物。

英文摘要：

Malignant mesothelioma is a universally lethal cancer that is increasing in incidence worldwide. There is a dearth of effective therapies, with only one treatment (pemetrexed and cisplatin combination chemotherapy) approved in the past 13 years. However, the past 5 years have witnessed an exponential growth in our understanding of mesothelioma pathobiology, which is set to revolutionize therapeutic strategies. From a genomic standpoint, mesothelioma is characterized by a preponderance of tumour suppressor alterations, for which novel therapies are currently in development. Other promising antitumour agents include inhibitors against angiogenesis, mesothelin and immune checkpoints, which are at various phases of clinical trial testing.

摘要翻译： 

恶性胸膜间皮瘤是一种全球发病率持续上升、普遍致死的恶性肿瘤。有效治疗手段匮乏，过去13年间仅有一种治疗方案（培美曲塞联合顺铂化疗）获批。然而，近5年来，学界对间皮瘤病理生物学的认知呈指数级增长，即将推动治疗策略革新。从基因组学角度看，间皮瘤以肿瘤抑制基因改变为主，针对这类改变的新疗法正在研发中。其他前景良好的抗肿瘤药物包括抗血管生成抑制剂、抗间皮素药物及免疫检查点抑制剂，目前均处于不同阶段的临床试验中。

原文链接：

Novel insights into mesothelioma biology and implications for therapy