表观遗传学药物+促分化诱导剂:治疗神经母细胞瘤

PNAS

2017-07-25Article

9.661

影响因子

原标题:联合表观遗传学和分化基础上的治疗,抑制神经母细胞瘤生长,HIF2α抑制肿瘤

① 神经母细胞瘤(NBM)的预后多样,从自发性消退到致命性进展;② 高风险NBM接受清髓化疗和造血干细胞移植,后续辅助维甲酸分化治疗,预后差;③ 系统性联合DNA去甲基化药物5-Aza-脱氧胞苷(AZA)和维甲酸(RA)治疗,快速诱导HIF2α相关的缺氧样转录应答,后续神经元基因表达增加、细胞周期基因表达减少,抑制肿瘤生长,延长生存期;④ 高水平HIF2α,与神经元分化基因表达及预后正相关,与MYCN扩增负相关,HIF2α在NBM中发挥抑癌基因作用。

神经母细胞瘤 分化 维甲酸

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Title:
Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

DOI:
10.1073/pnas.1700655114

Abstract & Authors展开

Abstract:
Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

All Authors:
Isabelle Westerlund,Yao Shi,Konstantinos Toskas,Stuart M Fell,Shuijie Li,Olga Surova,Erik Södersten,Per Kogner,Ulrika Nyman,Susanne Schlisio,Johan Holmberg

First Authors:
Isabelle Westerlund

Correspondence:
Johan Holmberg

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