5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft

Alexandra Borodovsky, Vafi Salmasi, Sevin Turcan, Armida W.M. Fabius, Gilson S. Baia, Charles G. Eberhart, Jon D. Weingart, Gary L. Gallia, Stephen B. Baylin, Timothy A. Chan, Gregory J. Riggins

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1737-1747
Number of pages11
JournalOncotarget
Volume4
Issue number10
DOIs
StatePublished - Oct 2013

Keywords

  • 5-azacytidine
  • Astrocytoma
  • IDH
  • Methylation
  • Progressive glioma
  • Xenograft

ASJC Scopus subject areas

  • Oncology

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