Evidence map›Paper›PMID 34246076›Full record

ArticleNeoplasia (New York, N.Y.)2021

EZH2i EPZ-6438 and HDACi vorinostat synergize with ONC201/TIC10 to activate integrated stress response, DR5, reduce H3K27 methylation, ClpX and promote apoptosis of multiple tumor types including DIPG.

Yiqun Zhang, Lanlan Zhou, Howard Safran, Robyn Borsuk, Rishi Lulla, Nikos Tapinos, Attila A Seyhan, Wafik S El-Deiry

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neoplasia (New York, N.Y.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
2.7field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

35 citing papers in PubMed, 43 citations in OpenAlex.

  1. Review
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  10. Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024
    Review
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  20. Therapeutic targeting of TRAIL death receptors.Biochemical Society transactions · 2023
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 2 institutions in 1 country.

Yiqun ZhangLaboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA.
Lanlan ZhouLaboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA.
Howard SafranThe Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, RI, USA.
Robyn BorsukLaboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Pediatric Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA.
Rishi LullaThe Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Pediatric Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA.
Nikos TapinosThe Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurosurgery, The Warren Alpert Medical School, Brown University, Providence, RI, USA.
Attila A SeyhanLaboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA.
Wafik S El-DeiryLaboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, RI, USA. Electronic address: wafik@brown.edu.
Brown University · USLifespan · US

Funding

TIC10 anti-tumor effect through regulation of Foxo3a and TRAILR01CA173453 · NCI · RESEARCH INST OF FOX CHASE CAN CTR · PI EL-DEIRY, WAFIK S. · 2013 to 2023
$4.3M
NCI NIH HHS R01 CA173453
6 · The paper itself

Abstract

ONC201/TIC10 activates TRAIL signaling through ATF4 and the integrated stress response (ISR). ONC201 demonstrated tumor regressions and disease stability in patients with histone H3K27M-mutated midline-glioma. H3K27M-mutation prevents H3K27-methylation on the mutated allele. EZH2 inhibitors (EZH2i) reduce H3K27 methylation and have anti-tumor effects. We hypothesized ONC201 sensitivity and tumor apoptosis may increase by reducing H3K27-methylation with EZH2i or HDACi as mimics of H3K27M-mutation. EZH2i EPZ-6438 (tazemetostat) or PF-06821497 and HDACi vorinostat were combined with ONC201 to treat multiple cancer cell lines and cell viability and histone modifications were analyzed. We observed synergistic effects towards cell viability in multiple cancers by EPZ-6438 or PF-06821497 plus ONC201 or triple therapy with vorinostat, EPZ-6438, and ONC201. EPZ-6438 and vorinostat synergized with ONC201 to enhance apoptosis. Activation of the ISR and TRAIL-DR5 were observed in cells treated with ONC201 -/+ epigenetic modulators. Knockdown of ATF4 reduced DR5 induction and apoptosis following EZH2i and ONC201 treatment of U251 glioma cells. mRNA expression of dopamine-receptors did not correlate with ONC201 sensitivity in the tumor cell lines tested (N = 12), including changes after epigenetic drugs. Dopamine did not rescue apoptosis by ONC201 in different tumor cell lines (N = 10) including 2 GBM, 3 DIPG and did not prevent DR5 activation or apoptosis. DRD2 agonist sumanirole did not protect brain tumor cells (N = 6 including 4 DIPG cell lines) from ONC201 reduction in viability. Although synergy was observed with ONC201 and vorinostat, there was no significant increase in H3K27 acetylation in cell lines including DIPG as compared to vorinostat alone, and in some cases the acetylation was less than vorinostat alone at 72 H. H3K27 methylation reduction correlated with synergy from combinations of either EPZ-6438 or vorinostat with ONC201 or triple combination. Our findings provide a rationale for combination of ONC201 and epigenetic modulators including triple therapy for in vivo and clinical testing in treatment of human malignancies including brain tumors and DIPG.

Indexed as

Antineoplastic AgentsApoptosisBenzamidesBiphenyl CompoundsCell Line, TumorCell SurvivalDrug SynergismEndopeptidase ClpEpigenesis, GeneticGene Expression Regulation, NeoplasticHistone Deacetylase InhibitorsHistonesHumansImidazolesMethylationMorpholinesAntineoplastic AgentsBenzamidesBiphenyl CompoundsCLPX protein, humanEndopeptidase ClpHistone Deacetylase InhibitorsHistonesImidazolesMorpholinesPyridinesPyridonesPyrimidinesReceptors, TNF-Related Apoptosis-Inducing LigandtazemetostatTIC10 compoundTNF-Related Apoptosis-Inducing LigandTNFRSF10B protein, humanTNFSF10 protein, humanVorinostatBreast cancerEZH2GliomaHDACHistone acetylationHistone methylationONC201

Identifiers

PMID34246076
PMCPMC8274300
OpenAlexW3178592991

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.