Therapeutic implications of melanoma heterogeneity.
Therapeutic implications of melanoma heterogeneity.
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DOI：
10.1111/exd.13002
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发表时间：
2016-07
影响因子：
3.6
通讯作者：
Boiko AD
中科院分区：
文献类型：
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作者：
Hachey SJ;Boiko AD
在过去的十年中，转移性黑色素瘤的治疗已经通过将分子见解转化为患者的治疗益处而发生了革命性变化。这些包括免疫治疗和小分子方法的进展，旨在破坏具有免疫原性抗原或基因突变的细胞。尽管取得了这些进展，但临床反应和最终疾病进展的持久性有限，这强调了需要更好地了解肿瘤发展的潜在机制。目前的靶向治疗部分基于肿瘤相对于突变癌基因或细胞表面抗原靶标主要是克隆性的基本原理而开发。然而，随着细胞分离和移植方法的进步，加上深度测序和突变检测技术，肿瘤是多克隆的已经变得越来越清楚。因此，敏感的恶性细胞通过治疗被根除，而剩余的肿瘤细胞群体通过隐藏或获得某些表观遗传和遗传异常而被赋予不同程度的抗性和存活优势。因此，肿瘤异质性代表了当前疗法成功应用的主要障碍。深入了解肿瘤多样性的细胞和分子方面，不仅有助于治疗靶点的开发和选择，还将促进精准医学的发展。在本观点中，我们将讨论肿瘤异质性对转移性黑色素瘤治疗的影响，并提出加速将科学发现转化为改善临床结局的方法。
Over the last decade, the treatment of metastatic melanoma has been revolutionized by the translation of molecular insights into therapeutic benefit for patients. These include advances in immune-therapeutic and small molecule approaches aimed at destroying cells with immunogenic antigens or gene mutations. Despite these advances, the limited durability of clinical response and eventual disease progression underscores a need for better understanding of mechanisms underlying tumor development. Current targeted therapies are developed partly based on the rationale that tumors are primarily clonal with respect to mutant oncogene or cell surface antigen target. However, with the advancement of cell isolation and transplantation approaches coupled with deep sequencing and mutation detection techniques, it has become increasingly clear that tumors are polyclonal. As a result, sensitive malignant cells are eradicated by treatment while the remaining tumor cell populations are conferred varying degrees of resistance and survival advantages by harboring or acquiring certain epigenetic and genetic abnormalities. Tumor heterogeneity thus represents a major obstacle to the successful application of current therapies. Gaining insights into the cellular and molecular aspects of tumor diversity will not only facilitate the development and selection of therapeutic targets but also promote the evolution of precision medicine. In this Viewpoint, we will discuss the implications of tumor heterogeneity for the treatment of metastatic melanoma and propose approaches to accelerate the translation of scientific discovery into improved clinical outcomes.