5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft
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 di...
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Published in | Oncotarget Vol. 4; no. 10; pp. 1737 - 1747 |
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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. |
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AbstractList | 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. 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. |
Author | Riggins, Gregory J Gallia, Gary L Borodovsky, Alexandra Salmasi, Vafi Fabius, Armida W M Baylin, Stephen B Weingart, Jon D Eberhart, Charles G Chan, Timothy A Turcan, Sevin Baia, Gilson S |
AuthorAffiliation | 2 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA 3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 1 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA |
AuthorAffiliation_xml | – name: 2 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA – name: 3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA – name: 1 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA – name: 4 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA |
Author_xml | – sequence: 1 givenname: Alexandra surname: Borodovsky fullname: Borodovsky, Alexandra organization: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA – sequence: 2 givenname: Vafi surname: Salmasi fullname: Salmasi, Vafi – sequence: 3 givenname: Sevin surname: Turcan fullname: Turcan, Sevin – sequence: 4 givenname: Armida W M surname: Fabius fullname: Fabius, Armida W M – sequence: 5 givenname: Gilson S surname: Baia fullname: Baia, Gilson S – sequence: 6 givenname: Charles G surname: Eberhart fullname: Eberhart, Charles G – sequence: 7 givenname: Jon D surname: Weingart fullname: Weingart, Jon D – sequence: 8 givenname: Gary L surname: Gallia fullname: Gallia, Gary L – sequence: 9 givenname: Stephen B surname: Baylin fullname: Baylin, Stephen B – sequence: 10 givenname: Timothy A surname: Chan fullname: Chan, Timothy A – sequence: 11 givenname: Gregory J surname: Riggins fullname: Riggins, Gregory J |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24077805$$D View this record in MEDLINE/PubMed |
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SubjectTerms | Animals Antimetabolites, Antineoplastic - pharmacology Azacitidine - pharmacology Brain Neoplasms - drug therapy Brain Neoplasms - enzymology Brain Neoplasms - genetics Brain Neoplasms - pathology Cell Differentiation - drug effects Cell Growth Processes - drug effects Cell Line, Tumor DNA Methylation - drug effects Female Glioma - drug therapy Glioma - enzymology Glioma - genetics Glioma - pathology Humans Immunohistochemistry Isocitrate Dehydrogenase - genetics Isocitrate Dehydrogenase - metabolism Male Mice Mice, Nude Mutation Research Paper Xenograft Model Antitumor Assays |
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Title | 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft |
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