1. Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells.
- Author
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Grinshtein N, Rioseco CC, Marcellus R, Uehling D, Aman A, Lun X, Muto O, Podmore L, Lever J, Shen Y, Blough MD, Cairncross GJ, Robbins SM, Jones SJ, Marra MA, Al-Awar R, Senger DL, and Kaplan DR
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, DNA Damage drug effects, Dexamethasone therapeutic use, Drug Synergism, Drug Therapy, Combination, Epigenesis, Genetic, Histone Deacetylase Inhibitors pharmacology, Humans, Mice, Mice, SCID, Molecular Targeted Therapy, Pyridones pharmacology, Small Molecule Libraries, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Drug Screening Assays, Antitumor methods, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Glioblastoma drug therapy, Histone Deacetylase Inhibitors therapeutic use, Pyridones therapeutic use
- Abstract
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.
- Published
- 2016
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