Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
Autor: | Richard Marcellus, Osamu Muto, Donna L. Senger, Rima Al-awar, Constanza Rioseco, Ahmed Aman, David L. Kaplan, Michael D. Blough, Marco A. Marra, Lauren Podmore, Greg J. Cairncross, Xueqing Lun, Steven J.M. Jones, David Uehling, Natalie Grinshtein, Stephen M. Robbins, Yaoqing Shen, Jake Lever |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Pyridones DNA damage Antineoplastic Agents Apoptosis Mice SCID UNC1999 Dexamethasone drug discovery Epigenesis Genetic Small Molecule Libraries Mice 03 medical and health sciences 0302 clinical medicine HDAC inhibitor In vivo Cell Line Tumor Animals Humans Medicine Enhancer of Zeste Homolog 2 Protein Molecular Targeted Therapy Epigenetics Cell Proliferation epigenetics Brain Neoplasms business.industry Drug discovery EZH2 glioblastoma Drug Synergism Xenograft Model Antitumor Assays In vitro Histone Deacetylase Inhibitors 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Drug Therapy Combination Drug Screening Assays Antitumor business Research Paper DNA Damage |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor, requiring the development of efficacious therapeutics. Towards this goal, we screened five genetically distinct patient-derived brain-tumor initiating cell lines (BTIC) with a unique collection of small molecule epigenetic modulators from the Structural Genomics Consortium (SGC). We identified multiple hits that inhibited the growth of BTICs in vitro, and further evaluated the therapeutic potential of EZH2 and HDAC inhibitors due to the high relevance of these targets for GBM. We found that the novel SAM-competitive EZH2 inhibitor UNC1999 exhibited low micromolar cytotoxicity in vitro on a diverse collection of BTIC lines, synergized with dexamethasone (DEX) and suppressed tumor growth in vivo in combination with DEX. In addition, a unique brain-penetrant class I HDAC inhibitor exhibited cytotoxicity in vitro on a panel of BTIC lines and extended survival in combination with TMZ in an orthotopic BTIC model in vivo. Finally, a combination of EZH2 and HDAC inhibitors demonstrated synergy in vitro by augmenting apoptosis and increasing DNA damage. Our findings identify key epigenetic modulators in GBM that regulate BTIC growth and survival and highlight promising combination therapies. |
Databáze: | OpenAIRE |
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