Demethylation Therapy as a Targeted Treatment for Human Papillomavirus-Associated Head and Neck Cancer
Demethylation Therapy as a Targeted Treatment for Human Papillomavirus-Associated Head and Neck Cancer
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DOI：
10.1158/1078-0432.ccr-17-1438
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发表时间：
2017-12-01
影响因子：
11.5
通讯作者：
Issaeva, Natalia
中科院分区：
文献类型：
--
作者：
Biktasova, Asel;Hajek, Michael;Issaeva, Natalia
目的：人乳头瘤病毒相关（HPV+）头颈部鳞状细胞癌（HNSCC） DNA甲基化可能对HPV癌基因的持续表达、肿瘤细胞增殖和生存具有重要意义。在这里，我们在临床前模型中确定了一种全局dna去甲基化剂5-氮杂胞苷（5-aza）对HPV+ HNSCC的活性，并在一项纳入HPV+ HNSCC患者的窗口试验中探索了它作为靶向治疗的可能性。实验设计：测定HNSCC细胞对5-aza处理的敏感性，然后用小鼠模型异种移植肿瘤检测5-aza的体内活性。最后，对入选窗口临床试验的患者的肿瘤样本进行分析，以确定5-aza治疗在HPV+ HNSCC患者中的活性。结果：临床试验和实验数据表明，5-aza可诱导HPV+ HNSCC的生长抑制和细胞死亡。5-aza降低了HPV基因的表达，稳定了p53，并诱导了HNSCC细胞和肿瘤中p53依赖性的凋亡。5-aza可抑制HPV+ HNSCC中基质金属蛋白酶（matrix metalloproteinases， MMP）的表达和活性，激活部分HPV+头颈部癌细胞的IFN应答，抑制HPV+异种移植肿瘤侵袭小鼠血管的能力。结论：5-aza可以作为标准细胞毒治疗的替代或补充，为hpv相关的HNSCC提供有效的治疗。(c) 2017 aacr。
Purpose: DNA methylation in human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels.Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. (C) 2017 AACR.