5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft.
5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft.
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DOI：
10.18632/oncotarget.1408
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Riggins GJ
中科院分区：
文献类型：
--
作者：
Borodovsky A;Salmasi V;Turcan S;Fabius AW;Baia GS;Eberhart CG;Weingart JD;Gallia GL;Baylin SB;Chan TA;Riggins GJ
异柠檬酸脱氢酶1的体细胞突变在低级别和进展性胶质瘤中很常见，其特征是突变酶能使α-酮戊二酸产生2-羟基戊二酸(2-HG)。2-HG是一种“肿瘤代谢物”，它竞争性地抑制依赖α-KG的双加氧酶，导致多种广泛的细胞变化，包括基因组DNA异常高甲基化和抑制细胞分化。尽管对IDH突变型胶质瘤的了解越来越多，但有效治疗方法的开发已被证明具有挑战性，部分原因是体内内源性突变型模型的匮乏。在这里，我们报道了一种内源性IDH1间变性星形细胞瘤模型的建立，该模型在体内快速生长，产生2-HG并表现出DNA高甲基化。利用该模型，我们在体内验证了FDA批准的去甲基化药物5-氮杂胞苷的临床前疗效和作用机制。长期应用5-氮胞苷可导致启动子DNA甲基化减少，诱导神经胶质细胞分化，细胞增殖减少，肿瘤生长明显减慢。肿瘤在14周时被观察到消退，随后在7周时没有显示出重新生长的迹象，尽管停止了治疗。这些结果对IDH突变型胶质瘤患者去甲基化药物的临床试验有一定的指导意义。
Somatic mutations in Isocitrate Dehydrogenase 1 (IDH1) are frequent in low grade and progressive gliomas and are characterized by the production of 2-hydroxyglutarate (2-HG) from α-ketoglutarate by the mutant enzyme. 2-HG is an “oncometabolite” that competitively inhibits α-KG dependent dioxygenases resulting in various widespread cellular changes including abnormal hypermethylation of genomic DNA and suppression of cellular differentiation. Despite the growing understanding of IDH mutant gliomas, the development of effective therapies has proved challenging in part due to the scarcity of endogenous mutant in vivo models. Here we report the generation of an endogenous IDH1 anaplastic astrocytoma model which rapidly grows in vivo, produces 2-HG and exhibits DNA hypermethylation. Using this model, we have demonstrated the preclinical efficacy and mechanism of action of the FDA approved demethylating drug 5-azacytidine in vivo. Long term administration of 5-azacytidine resulted in reduction of DNA methylation of promoter loci, induction of glial differentiation, reduction of cell proliferation and a significant reduction in tumor growth. Tumor regression was observed at 14 weeks and subsequently showed no signs of re-growth at 7 weeks despite discontinuation of therapy. These results have implications for clinical trials of demethylating agents for patients with IDH mutated gliomas.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
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Thompson, Craig B.
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50.3
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Melnick A
影响因子：
20.3
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通讯作者：
Morgan, Gareth J.
影响因子：
7
作者：
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通讯作者：
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