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DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA
Diffuse midline glioma is an aggressive brain tumor with a median age at diagnosis of 6.3 years and 5-year survival rate of 2.2%.The defining histone mutation H3K27M precludes docking of a protein responsible for epigenetic modification resulting in erroneously accessible chromatin and subsequent tr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260195/ http://dx.doi.org/10.1093/neuonc/noad073.093 |
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author | Casillo, Stephanie Gatesman, Taylor Chilukuri, Akanksha Jane, Esther Premkumar, Daniel Barber, Callie Halbert, Matthew Cruz, Andrea Mullett, Steven Michel, Joshua Chang, Yue-Fang MichaelRaj, Antony Lieberman, Frank Felker, James Shiva, Sruti Abdullah, Kalil Zinn, Pascal Friedlander, Robert Abel, Taylor Venneti, Sriram Mack, Stephen Wendell, Stacy Pollack, Ian Agnihotri, Sameer |
author_facet | Casillo, Stephanie Gatesman, Taylor Chilukuri, Akanksha Jane, Esther Premkumar, Daniel Barber, Callie Halbert, Matthew Cruz, Andrea Mullett, Steven Michel, Joshua Chang, Yue-Fang MichaelRaj, Antony Lieberman, Frank Felker, James Shiva, Sruti Abdullah, Kalil Zinn, Pascal Friedlander, Robert Abel, Taylor Venneti, Sriram Mack, Stephen Wendell, Stacy Pollack, Ian Agnihotri, Sameer |
author_sort | Casillo, Stephanie |
collection | PubMed |
description | Diffuse midline glioma is an aggressive brain tumor with a median age at diagnosis of 6.3 years and 5-year survival rate of 2.2%.The defining histone mutation H3K27M precludes docking of a protein responsible for epigenetic modification resulting in erroneously accessible chromatin and subsequent transcription of oncogenic pathways, including the RAS-MERK5-ERK5 signaling cascade. To determine which oncogenic processes are regulated by extracellular signal-regulated kinase 5 (ERK5), gene-set enrichment analysis of patient-derived datasets demonstrated gene networks involved in glycolysis to be enriched with ERK5 expression. In confirmation, loss of ERK5 via shRNA interference reduced cell proliferation and glycolysis in DIPG IV and SF8628 cells. Reintroduction of ERK5 wildtype (WT) into ERK5 knockdown lines rescued cell proliferation and glycolysis, while the addition of ERK5 kinase dead domain (KDD) only partially rescued these survival and metabolic defects. Targeted evaluation of glycolysis enzyme expression via qRT-PCR revealed a direct relationship between ERK5 and proglycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Mechanistically, ERK5 activation of PFKFB3 was mediated by activation of transcriptional factor myocyte enhancer factor 2A (MEF2A) as demonstrated by coimmunoprecipitation and luciferase promoter assays. Expression of PFKFB3 was elevated at both the mRNA and protein level in DMG patient-derived samples. Genetic knockdown of PFKFB3 via shRNA interference resulted in reduced proliferation and glycolysis in DIPG IV and SF8628 cells. Similarly, pharmacologic inhibition of PFKFB3 with small molecule inhibitor PFK-158 capitulated these results. This inhibitor demonstrated blood brain barrier penetrance in silico and extended survival of in vivo mouse models. Multitargeted drug therapy against both ERK5 and PFKFB3 produced a synergetic in vitro response with increased sensitivity of these cells to apoptosis compared to single treatment alone. In conclusion, these results support ERK5 regulation of glycolysis through the critical metabolic effector PFKFB3. Multitargeted drug therapy against this axis represents a therapeutic vulnerability in pediatric diffuse midline glioma. |
format | Online Article Text |
id | pubmed-10260195 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102601952023-06-13 DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA Casillo, Stephanie Gatesman, Taylor Chilukuri, Akanksha Jane, Esther Premkumar, Daniel Barber, Callie Halbert, Matthew Cruz, Andrea Mullett, Steven Michel, Joshua Chang, Yue-Fang MichaelRaj, Antony Lieberman, Frank Felker, James Shiva, Sruti Abdullah, Kalil Zinn, Pascal Friedlander, Robert Abel, Taylor Venneti, Sriram Mack, Stephen Wendell, Stacy Pollack, Ian Agnihotri, Sameer Neuro Oncol Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG Diffuse midline glioma is an aggressive brain tumor with a median age at diagnosis of 6.3 years and 5-year survival rate of 2.2%.The defining histone mutation H3K27M precludes docking of a protein responsible for epigenetic modification resulting in erroneously accessible chromatin and subsequent transcription of oncogenic pathways, including the RAS-MERK5-ERK5 signaling cascade. To determine which oncogenic processes are regulated by extracellular signal-regulated kinase 5 (ERK5), gene-set enrichment analysis of patient-derived datasets demonstrated gene networks involved in glycolysis to be enriched with ERK5 expression. In confirmation, loss of ERK5 via shRNA interference reduced cell proliferation and glycolysis in DIPG IV and SF8628 cells. Reintroduction of ERK5 wildtype (WT) into ERK5 knockdown lines rescued cell proliferation and glycolysis, while the addition of ERK5 kinase dead domain (KDD) only partially rescued these survival and metabolic defects. Targeted evaluation of glycolysis enzyme expression via qRT-PCR revealed a direct relationship between ERK5 and proglycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Mechanistically, ERK5 activation of PFKFB3 was mediated by activation of transcriptional factor myocyte enhancer factor 2A (MEF2A) as demonstrated by coimmunoprecipitation and luciferase promoter assays. Expression of PFKFB3 was elevated at both the mRNA and protein level in DMG patient-derived samples. Genetic knockdown of PFKFB3 via shRNA interference resulted in reduced proliferation and glycolysis in DIPG IV and SF8628 cells. Similarly, pharmacologic inhibition of PFKFB3 with small molecule inhibitor PFK-158 capitulated these results. This inhibitor demonstrated blood brain barrier penetrance in silico and extended survival of in vivo mouse models. Multitargeted drug therapy against both ERK5 and PFKFB3 produced a synergetic in vitro response with increased sensitivity of these cells to apoptosis compared to single treatment alone. In conclusion, these results support ERK5 regulation of glycolysis through the critical metabolic effector PFKFB3. Multitargeted drug therapy against this axis represents a therapeutic vulnerability in pediatric diffuse midline glioma. Oxford University Press 2023-06-12 /pmc/articles/PMC10260195/ http://dx.doi.org/10.1093/neuonc/noad073.093 Text en © The Author(s) 2023. 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 | Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG Casillo, Stephanie Gatesman, Taylor Chilukuri, Akanksha Jane, Esther Premkumar, Daniel Barber, Callie Halbert, Matthew Cruz, Andrea Mullett, Steven Michel, Joshua Chang, Yue-Fang MichaelRaj, Antony Lieberman, Frank Felker, James Shiva, Sruti Abdullah, Kalil Zinn, Pascal Friedlander, Robert Abel, Taylor Venneti, Sriram Mack, Stephen Wendell, Stacy Pollack, Ian Agnihotri, Sameer DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA |
title | DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA |
title_full | DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA |
title_fullStr | DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA |
title_full_unstemmed | DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA |
title_short | DIPG-46. TARGETING THE METABOLIC ERK5-PFKFB3 AXIS IN PEDIATRIC DIFFUSE MIDLINE GLIOMA |
title_sort | dipg-46. targeting the metabolic erk5-pfkfb3 axis in pediatric diffuse midline glioma |
topic | Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260195/ http://dx.doi.org/10.1093/neuonc/noad073.093 |
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