TY - JOUR
T1 - Evaluation of a DNA demethylating agent in combination with all-trans retinoic acid for IDH1-mutant gliomas
AU - Da Costa Rosa, Marina
AU - Yamashita, Alex Shimura
AU - Riggins, Gregory J.
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - Background: Isocitrate Dehydrogenase 1/2 (IDH1/2) mutations are diagnostic for Astrocytoma or Oligodendroglioma, IDH-mutant. In these IDH-mutant gliomas, retinoic acid-related gene expression is commonly silenced by DNA hypermethylation. DNA demethylating agents can epigenetically reprogram IDH-mutant cells and reduce proliferation, likely by re-expression of silenced tumor suppressor pathways. We hypothesized that DNA demethylation might restore the retinoic acid pathway and slow tumor growth. This was the rationale for a preclinical evaluation combining the DNA demethylating agent, 5-Azacytidine (5-Aza), and retinoic acid pathway activation with all-trans retinoic acid (atRA) in IDH-mutant glioma. Methods: In this study, we evaluated the effect of 5-Aza and atRA combination on cell proliferation, apoptosis, and gene expression in human glioma cells. In addition, the efficacy of this combination was tested in patient-derived xenograft (PDX) bearing the IDH1R132H mutation, utilizing subcutaneous and orthotopic models. Results: 5-Aza reduced the DNA methylation profile and increased the gene expression of retinoic acid-related genes. Combination of 5-Aza and atRA reduced cell growth, increased differentiation marker expression, and apoptosis in IDH1R132H glioma cells. Mechanistically, 5-Aza sensitized IDHIR132H glioma cells to atRA via upregulation of the retinoic acid pathway. Importantly, the drug combination reduced significantly the growth rate of subcutaneous tumors, but in an orthotopic mouse model, the combination did not improve survival and 5-Aza alone provided the best survival benefit. Conclusion: Use of DNA demethylating agent in combination with retinoids shows promise, but further optimization and preclinical studies are required for treatment of intracranial IDH-mutant gliomas.
AB - Background: Isocitrate Dehydrogenase 1/2 (IDH1/2) mutations are diagnostic for Astrocytoma or Oligodendroglioma, IDH-mutant. In these IDH-mutant gliomas, retinoic acid-related gene expression is commonly silenced by DNA hypermethylation. DNA demethylating agents can epigenetically reprogram IDH-mutant cells and reduce proliferation, likely by re-expression of silenced tumor suppressor pathways. We hypothesized that DNA demethylation might restore the retinoic acid pathway and slow tumor growth. This was the rationale for a preclinical evaluation combining the DNA demethylating agent, 5-Azacytidine (5-Aza), and retinoic acid pathway activation with all-trans retinoic acid (atRA) in IDH-mutant glioma. Methods: In this study, we evaluated the effect of 5-Aza and atRA combination on cell proliferation, apoptosis, and gene expression in human glioma cells. In addition, the efficacy of this combination was tested in patient-derived xenograft (PDX) bearing the IDH1R132H mutation, utilizing subcutaneous and orthotopic models. Results: 5-Aza reduced the DNA methylation profile and increased the gene expression of retinoic acid-related genes. Combination of 5-Aza and atRA reduced cell growth, increased differentiation marker expression, and apoptosis in IDH1R132H glioma cells. Mechanistically, 5-Aza sensitized IDHIR132H glioma cells to atRA via upregulation of the retinoic acid pathway. Importantly, the drug combination reduced significantly the growth rate of subcutaneous tumors, but in an orthotopic mouse model, the combination did not improve survival and 5-Aza alone provided the best survival benefit. Conclusion: Use of DNA demethylating agent in combination with retinoids shows promise, but further optimization and preclinical studies are required for treatment of intracranial IDH-mutant gliomas.
KW - 5-Azacytidine
KW - DNA methylation
KW - IDH1 mutation
KW - glioma
KW - retinoic acid
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U2 - 10.1093/neuonc/noab263
DO - 10.1093/neuonc/noab263
M3 - Article
C2 - 34850159
AN - SCOPUS:85129997457
SN - 1522-8517
VL - 24
SP - 711
EP - 723
JO - Neuro-oncology
JF - Neuro-oncology
IS - 5
ER -