Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells
Why this work is in the frame
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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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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.000 | 0.000 |
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 it