1. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.
- Author
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Ehteda A, Simon S, Franshaw L, Giorgi FM, Liu J, Joshi S, Rouaen JRC, Pang CNI, Pandher R, Mayoh C, Tang Y, Khan A, Ung C, Tolhurst O, Kankean A, Hayden E, Lehmann R, Shen S, Gopalakrishnan A, Trebilcock P, Gurova K, Gudkov AV, Norris MD, Haber M, Vittorio O, Tsoli M, and Ziegler DS
- Subjects
- Acetylation, Animals, Brain Stem Neoplasms genetics, Brain Stem Neoplasms mortality, Brain Stem Neoplasms pathology, Carbazoles pharmacology, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Child, Chromatin chemistry, Chromatin metabolism, DNA-Binding Proteins metabolism, Diffuse Intrinsic Pontine Glioma genetics, Diffuse Intrinsic Pontine Glioma mortality, Diffuse Intrinsic Pontine Glioma pathology, Drug Synergism, E2F1 Transcription Factor genetics, E2F1 Transcription Factor metabolism, Epigenome, High Mobility Group Proteins metabolism, Histones antagonists & inhibitors, Histones metabolism, Humans, Methylation, Mice, Neuroglia metabolism, Neuroglia pathology, Panobinostat pharmacology, Primary Cell Culture, Retinoblastoma Protein genetics, Retinoblastoma Protein metabolism, Signal Transduction, Survival Analysis, Transcription Factors genetics, Transcription Factors metabolism, Transcriptional Elongation Factors metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Brain Stem Neoplasms drug therapy, DNA-Binding Proteins genetics, Diffuse Intrinsic Pontine Glioma drug therapy, Epigenesis, Genetic, High Mobility Group Proteins genetics, Histones genetics, Neuroglia drug effects, Transcriptional Elongation Factors genetics
- Abstract
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG., Competing Interests: Declaration of interests K.G. and A.V.G. are co-inventors on patents describing CBL0137. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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