Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
Bibliographic record
Abstract
// Natalie Grinshtein 1 , Constanza C. Rioseco 1 , Richard Marcellus 2 , David Uehling 2 , Ahmed Aman 2 , Xueqing Lun 3 , Osamu Muto 1 , Lauren Podmore 1 , Jake Lever 4 , Yaoqing Shen 4 , Michael D. Blough 3 , Greg J. Cairncross 3 , Stephen M. Robbins 3 , Steven J. Jones 4, 5, 6 , Marco A. Marra 4, 5 , Rima Al-Awar 2 , Donna L. Senger 3 , David R. Kaplan 1, 7 1 Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada 2 Drug Discovery Group, Ontario Institute for Cancer Research, Toronto, ON, Canada 3 Arnie Charbonneau Cancer Institute, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada 4 Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada 5 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada 6 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia 7 Department of Molecular Genetics, University of Toronto, Toronto, ON Canada Correspondence to: David R. Kaplan, email: dkaplan@sickkids.ca Keywords: glioblastoma, drug discovery, epigenetics, UNC1999, HDAC inhibitor Received: March 17, 2016 Accepted: July 07, 2016 Published: July 18, 2016 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".