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STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma

BACKGROUND: H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. METHODS: We screened a library of drugs either FDA-approved or in clinical tria...

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Autores principales: Zhang, Liang, Nesvick, Cody L, Day, Charlie A, Choi, Jonghoon, Lu, Victor M, Peterson, Timothy, Power, Erica A, Anderson, Jacob B, Hamdan, Feda H, Decker, Paul A, Simons, Renae, Welby, John P, Siada, Ruby, Ge, Jizhi, Kaptzan, Tatiana, Johnsen, Steven A, Hinchcliffe, Edward H, Daniels, David J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9527528/
https://www.ncbi.nlm.nih.gov/pubmed/35397475
http://dx.doi.org/10.1093/neuonc/noac093
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author Zhang, Liang
Nesvick, Cody L
Day, Charlie A
Choi, Jonghoon
Lu, Victor M
Peterson, Timothy
Power, Erica A
Anderson, Jacob B
Hamdan, Feda H
Decker, Paul A
Simons, Renae
Welby, John P
Siada, Ruby
Ge, Jizhi
Kaptzan, Tatiana
Johnsen, Steven A
Hinchcliffe, Edward H
Daniels, David J
author_facet Zhang, Liang
Nesvick, Cody L
Day, Charlie A
Choi, Jonghoon
Lu, Victor M
Peterson, Timothy
Power, Erica A
Anderson, Jacob B
Hamdan, Feda H
Decker, Paul A
Simons, Renae
Welby, John P
Siada, Ruby
Ge, Jizhi
Kaptzan, Tatiana
Johnsen, Steven A
Hinchcliffe, Edward H
Daniels, David J
author_sort Zhang, Liang
collection PubMed
description BACKGROUND: H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. METHODS: We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. RESULTS: Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. CONCLUSIONS: STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.
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spelling pubmed-95275282022-10-03 STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma Zhang, Liang Nesvick, Cody L Day, Charlie A Choi, Jonghoon Lu, Victor M Peterson, Timothy Power, Erica A Anderson, Jacob B Hamdan, Feda H Decker, Paul A Simons, Renae Welby, John P Siada, Ruby Ge, Jizhi Kaptzan, Tatiana Johnsen, Steven A Hinchcliffe, Edward H Daniels, David J Neuro Oncol Basic and Translational Investigations BACKGROUND: H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. METHODS: We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. RESULTS: Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. CONCLUSIONS: STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials. Oxford University Press 2022-04-09 /pmc/articles/PMC9527528/ /pubmed/35397475 http://dx.doi.org/10.1093/neuonc/noac093 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Basic and Translational Investigations
Zhang, Liang
Nesvick, Cody L
Day, Charlie A
Choi, Jonghoon
Lu, Victor M
Peterson, Timothy
Power, Erica A
Anderson, Jacob B
Hamdan, Feda H
Decker, Paul A
Simons, Renae
Welby, John P
Siada, Ruby
Ge, Jizhi
Kaptzan, Tatiana
Johnsen, Steven A
Hinchcliffe, Edward H
Daniels, David J
STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma
title STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma
title_full STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma
title_fullStr STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma
title_full_unstemmed STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma
title_short STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma
title_sort stat3 is a biologically relevant therapeutic target in h3k27m-mutant diffuse midline glioma
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9527528/
https://www.ncbi.nlm.nih.gov/pubmed/35397475
http://dx.doi.org/10.1093/neuonc/noac093
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