Evidence map›Paper›PMID 39501501›Full record

ArticleCancer medicine2024

Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.

Janith A Seneviratne, Daenikka Ravindrarajah, Daniel R Carter, Vicki Zhai, Amit Lalwani, Sukriti Krishan, Anushree Balachandran, Ernest Ng, Ruby Pandher, Matthew Wong and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
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

2 citing papers in PubMed.

  1. Article
  2. Article
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

18 authors.

Janith A SeneviratneChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Daenikka RavindrarajahChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Daniel R CarterChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Vicki ZhaiChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Amit LalwaniChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Sukriti KrishanChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Anushree BalachandranChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Ernest NgChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Ruby PandherChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Matthew WongChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Tracy L NeroDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
Shudong WangCentre for Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
Murray D NorrisChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Michelle HaberChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Tao LiuChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
Michael W ParkerDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
Belamy B CheungChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.ORCID https://orcid.org/0000-0001-8784-860X
Glenn M MarshallChildren's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.

Funding

Cancer Australia 1123235Cancer Council NSW PG-11-06Cancer Council NSW RG21-08Cancer Council NSW RG214491Cancer Institute NSW 10/TPG/1-13Kids' Cancer Project RG213283Kids' Cancer Project RG231618National Health and Medical Research Council APP1016699National Health and Medical Research Council APP1125171National Health and Medical Research Council RG220538Neuroblastoma Australia RG231619
6 · The paper itself

Abstract

backgroundThe child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy.

methodsWe performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations.

resultsWe found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4-mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents.

conclusionOur results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.

Indexed as

Enhancer of Zeste Homolog 2 ProteinHistone-Lysine N-MethyltransferaseNeuroblastomaActivating Transcription Factor 4AnimalsAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCell ProliferationDrug SynergismEndoplasmic Reticulum StressEnzyme InhibitorsHumansIndazolesMicePyridonesXenograft Model Antitumor AssaysActivating Transcription Factor 4ATF4 protein, humanDOT1L protein, humanEnhancer of Zeste Homolog 2 ProteinEnzyme InhibitorsEZH2 protein, humanGSK343Histone-Lysine N-MethyltransferaseIndazolesPyridonesbiomarkerscancer biologychromatin modifications and dynamicsepigeneticsmolecular biologyneuroblastoma

Identifiers

PMID39501501
PMCPMC11538032

What OpenQuestion holds

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LicenceCC BY
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.