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.
Highlights
Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor
Compounds targeting multiple epigenetic targets were identified that suppressed brain tumor-initiating cells (BTICs) health at low micromolar or nanomolar ranges, including histone methyl transferases (G9A, enhancer of zeste homolog 2 (EZH2), SMYD2), BET bromodomains, histone demethylase (JMJD3) and histone deacetylases (HDACs)
Since UNC1999 increased the expression of the autophagic marker LC3B II, we suggest that autophagy rather than necroptosis or apoptosis is the mechanism of BTIC cell death by this compound
Summary
The standard-of-care treatment includes surgical resection, followed by radiotherapy and chemotherapy with the alkylating agent temozolomide (TMZ) Despite this multifaceted therapy, prognosis for GBM patients remains poor with a median survival of only 14.6 months [1]. Recent genome-wide genomic and epigenomic analyses have revealed that 46% of 291 GBM samples tested have at least one somatic mutation in genes associated with chromatin modification [11]. Epigenetic alterations, those involving enzymatic modifications of either DNA or associated histone proteins are currently being exploited for therapeutic drug targeting. At the moment there is limited knowledge regarding the mechanisms through which epigenetic modifiers function in GBM, and the possibility of therapeutic targeting has not been rigorously tested for this tumor
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