title: Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells.
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.
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Grinshtein
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Constanza C
authors.initials: CC
authors.lastname: Rioseco
authors.affiliation: Drug Discovery Group, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Marcellus
authors.affiliation: Drug Discovery Group, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Uehling
authors.affiliation: Drug Discovery Group, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aman
authors.affiliation: Arnie Charbonneau Cancer Institute, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Osamu
authors.initials: O
authors.lastname: Muto
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Lauren
authors.initials: L
authors.lastname: Podmore
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.
authors.forename: Jake
authors.initials: J
authors.lastname: Lever
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.
authors.forename: Yaoqing
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Arnie Charbonneau Cancer Institute, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Blough
authors.affiliation: Arnie Charbonneau Cancer Institute, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Cairncross
authors.affiliation: Arnie Charbonneau Cancer Institute, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Robbins
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Jones
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Drug Discovery Group, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.affiliation: Arnie Charbonneau Cancer Institute, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Senger
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D003907:Dexamethasone / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors*; D044127:Epigenesis, Genetic; D005909:Glioblastoma / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D054852:Small Molecule Libraries; D023041:Xenograft Model Antitumor Assays; D001549:Benzamides; D007191:Indazoles; D010879:Piperazines
chemical_list: D000970:Antineoplastic Agents; D003907:Dexamethasone; D000071221:Enhancer of Zeste Homolog 2 Protein; D056572:Histone Deacetylase Inhibitors; D011728:Pyridones; D054852:Small Molecule Libraries; C000619732:UNC1999; D001549:Benzamides; D007191:Indazoles; D010879:Piperazines; C498409:EZH2 protein, human
keywords: HDAC inhibitor; UNC1999; drug discovery; epigenetics; glioblastoma