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DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Imipridones induce apoptosis in cancer via p53 independent upregulation of TNF-related apoptosis inducing ligand (TRAIL) pathway and its proapoptotic receptor DR5. ONC201, a first-in-class imipridone, is being evaluated alone and with radiotherapy for children with H3K27M mutant diffuse glioma. We s...

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Autores principales: Borsuk, Robyn, Zhou, Lanlan, Zhang, Yiqun, Prabhua, Varun, Allen, Joshua, Oster, Wolfgang, Tapinos, Nikos, Lulla, Rishi R, El-Deiry, Wafik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715116/
http://dx.doi.org/10.1093/neuonc/noaa222.107
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author Borsuk, Robyn
Zhou, Lanlan
Zhang, Yiqun
Prabhua, Varun
Allen, Joshua
Oster, Wolfgang
Tapinos, Nikos
Lulla, Rishi R
El-Deiry, Wafik
author_facet Borsuk, Robyn
Zhou, Lanlan
Zhang, Yiqun
Prabhua, Varun
Allen, Joshua
Oster, Wolfgang
Tapinos, Nikos
Lulla, Rishi R
El-Deiry, Wafik
author_sort Borsuk, Robyn
collection PubMed
description Imipridones induce apoptosis in cancer via p53 independent upregulation of TNF-related apoptosis inducing ligand (TRAIL) pathway and its proapoptotic receptor DR5. ONC201, a first-in-class imipridone, is being evaluated alone and with radiotherapy for children with H3K27M mutant diffuse glioma. We sought to determine if ONC201 and its imipridone analogs (ONC206, ONC212) are synergistic with other chemotherapy agents. Seven patient-derived DIPG cell lines, six H3.3K27M mutant (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SF8628) and one H3.1K27M mutant (SU-DIPG-36) were grown in culture and exposed to ONC201, ONC206, and ONC212 alone and in combination with histone de-acetylase inhibitors (HDACi) or etoposide. A dose-dependent response to ONC201, ONC206, and ONC212 was demonstrated in all cell lines, with mean IC50 values of 1.46 µM, 0.11 µM, and 0.03 µM respectively. ONC206 and ONC212 induced apoptosis measured by increased expression of cleaved PARP and ISR by increased expression ATF4. In two cell lines, synergy studies revealed combination indices (CI) < 1 for ONC206 and etoposide, with a best CI of 0.62 in SU-DIPG-IV and 0.46 in SU-DIPG-25. Synergy was also observed between ONC201 and etoposide (CI 0.46) and ONC201 and panobinostat (CI 0.01). Imipridones and analogs were superior to panobinostat and etoposide in triggering apoptosis as measured by sub-G1 phase content. Additional synergy and mechanistic analyses are ongoing and will be reported. Our results suggest that H3K27M mutant DIPG cells demonstrate increased sensitivity to imipridone analogs (ONC206 and ONC212) when compared to ONC201. Combinational strategies with etoposide or HDACi should be considered for clinical translation.
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spelling pubmed-77151162020-12-09 DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) Borsuk, Robyn Zhou, Lanlan Zhang, Yiqun Prabhua, Varun Allen, Joshua Oster, Wolfgang Tapinos, Nikos Lulla, Rishi R El-Deiry, Wafik Neuro Oncol Diffuse Midline Glioma/DIPG Imipridones induce apoptosis in cancer via p53 independent upregulation of TNF-related apoptosis inducing ligand (TRAIL) pathway and its proapoptotic receptor DR5. ONC201, a first-in-class imipridone, is being evaluated alone and with radiotherapy for children with H3K27M mutant diffuse glioma. We sought to determine if ONC201 and its imipridone analogs (ONC206, ONC212) are synergistic with other chemotherapy agents. Seven patient-derived DIPG cell lines, six H3.3K27M mutant (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SF8628) and one H3.1K27M mutant (SU-DIPG-36) were grown in culture and exposed to ONC201, ONC206, and ONC212 alone and in combination with histone de-acetylase inhibitors (HDACi) or etoposide. A dose-dependent response to ONC201, ONC206, and ONC212 was demonstrated in all cell lines, with mean IC50 values of 1.46 µM, 0.11 µM, and 0.03 µM respectively. ONC206 and ONC212 induced apoptosis measured by increased expression of cleaved PARP and ISR by increased expression ATF4. In two cell lines, synergy studies revealed combination indices (CI) < 1 for ONC206 and etoposide, with a best CI of 0.62 in SU-DIPG-IV and 0.46 in SU-DIPG-25. Synergy was also observed between ONC201 and etoposide (CI 0.46) and ONC201 and panobinostat (CI 0.01). Imipridones and analogs were superior to panobinostat and etoposide in triggering apoptosis as measured by sub-G1 phase content. Additional synergy and mechanistic analyses are ongoing and will be reported. Our results suggest that H3K27M mutant DIPG cells demonstrate increased sensitivity to imipridone analogs (ONC206 and ONC212) when compared to ONC201. Combinational strategies with etoposide or HDACi should be considered for clinical translation. Oxford University Press 2020-12-04 /pmc/articles/PMC7715116/ http://dx.doi.org/10.1093/neuonc/noaa222.107 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://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 Diffuse Midline Glioma/DIPG
Borsuk, Robyn
Zhou, Lanlan
Zhang, Yiqun
Prabhua, Varun
Allen, Joshua
Oster, Wolfgang
Tapinos, Nikos
Lulla, Rishi R
El-Deiry, Wafik
DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
title DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
title_full DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
title_fullStr DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
title_full_unstemmed DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
title_short DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
title_sort dipg-62. preclinical evaluation of imipridone-based combination therapies in pediatric h3k27m mutant diffuse intrinsic pontine glioma (dipg)
topic Diffuse Midline Glioma/DIPG
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715116/
http://dx.doi.org/10.1093/neuonc/noaa222.107
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