Functional Cloning of Recurrence-specific Antigens Identifies Molecular Targets to Treat Tumor Relapse
Functional Cloning of Recurrence-specific Antigens Identifies Molecular Targets to Treat Tumor Relapse
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DOI：
10.1038/mt.2013.116
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发表时间：
2013-08-01
影响因子：
12.4
通讯作者：
Vile, Richard
中科院分区：
文献类型：
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作者：
Boisgerault, Nicolas;Kottke, Timothy;Vile, Richard
治疗诱导的休眠后复发性肿瘤的积极再生代表了恶性疾病治疗的主要临床挑战。我们之前报道过，复发性前列腺肿瘤经历了完全的宏观消退，随后又发生了积极的再生，可以用源自复发性肿瘤细胞的水泡性口炎病毒（VSV）表达的 cDNA 文库来治愈。通过筛选复发源性保护性 VSV-cDNA 文库，我们将拓扑异构酶-II α (TOPO-II α) 鉴定为复发特异性肿瘤抗原，可以打破其耐受性。在两种不同类型的肿瘤（前列腺癌和黑色素瘤）中，逃避了两种不同一线治疗（免疫疗法或化疗）的肿瘤复发，与原发肿瘤对应物相比，TOPO-II α显着过度表达，这赋予了复发肿瘤对阿霉素（DOX）化疗的新敏感性。在体内利用联合疗法来治愈小鼠，否则在两种模型的初级治疗均未达到最佳效果后，小鼠可能会复发。我们的数据显示，与原发性肿瘤相比，复发性肿瘤（跨组织学和初次治疗）表达不同的抗原，可以使用 VSV-cDNA 文库技术进行识别。这些结果表明，设计一些常见的二线疗法来对抗各种肿瘤复发是可能的，在某些情况下使用对原发肿瘤没有明显活性的药物。
Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-II alpha (TOPO-II alpha) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-II alpha compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors-across histologies and primary treatments-express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.