期刊
ONCOTARGET
卷 4, 期 10, 页码 1737-1747出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1408
关键词
IDH; 5-azacytidine; progressive glioma; xenograft; astrocytoma; methylation
资金
- Conrad N. Hilton Foundation
- Virginia and D. K. Ludwig Fund for Cancer Research
- NIH [P30 CA006973, UL1 RR025005, 1S10RR026824-01]
- Irving J. Sherman Research Professorship in Neurosurgery
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 alpha-ketoglutarate by the mutant enzyme. 2-HG is an oncometabolite that competitively inhibits alpha-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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