Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma
Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma
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DOI：
10.1158/2159-8290.cd-15-1336
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发表时间：
2016-03-01
期刊：
影响因子：
28.2
通讯作者：
Marais, Richard
中科院分区：
文献类型：
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作者：
Girotti, Maria Romina;Gremel, Gabriela;Marais, Richard
靶向治疗和免疫治疗已经改变了黑色素瘤的护理，将中位生存期从9个月延长到25个月以上，但大多数患者仍然死于他们的疾病。精准医疗的目的是为个体患者量身定制护理并改善结果。为此，我们制定了方案，以促进晚期黑色素瘤患者的个性化治疗决策，分析了来自214名患者的364份样本。全外显子组测序（WES）和循环肿瘤DNA（ctDNA）的靶向测序使我们能够监测对治疗的反应，并识别和跟踪耐药机制。肿瘤的WES揭示了针对BRAF野生型和耐药BRAF突变型肿瘤的潜在假设驱动的治疗策略，然后在患者来源的异种移植物（PDX）中验证。我们还开发了循环肿瘤细胞来源的异种移植物（CDX），作为PDX的替代品，当肿瘤难以接近或难以活检时。因此，我们描述了一个强大的技术平台，精准医疗的患者与melanoma.Significance：虽然最近的发展已经彻底改变了黑色素瘤的护理，大多数患者仍然死于他们的疾病。为了进一步改善黑色素瘤的结果，我们开发了一个强大的精准医学平台来监测患者的反应，并为没有反应或对当前治疗产生耐药性的患者识别和验证假设驱动的治疗。(C)2015年AACR。
Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from similar to 9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma.SIGNIFICANCE: Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments. (C) 2015 AACR.