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DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA

Diffuse Midline Gliomas (DMG) are amongst the most lethal pediatric brain tumors. Children diagnosed with DMG face a grim prognosis of 9-11 months from diagnosis. Over 85% of DMG patients harbor mutation affecting histone-encoding genes (H3.1K27M, H3.3K27M) leading to genome hypomethylation and tran...

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Autores principales: Ciani, Ludovica, Laternser, Sandra, Kritzer, Bettina, Hasler, Kerstin, Przystal, Justyna M, Velagapudi, Mohana R, Alonso, Marta M, Zalacain, Marta, Müller, Sabine, Nazarian, Javad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260095/
http://dx.doi.org/10.1093/neuonc/noad073.069
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author Ciani, Ludovica
Laternser, Sandra
Kritzer, Bettina
Hasler, Kerstin
Przystal, Justyna M
Velagapudi, Mohana R
Alonso, Marta M
Zalacain, Marta
Müller, Sabine
Nazarian, Javad
author_facet Ciani, Ludovica
Laternser, Sandra
Kritzer, Bettina
Hasler, Kerstin
Przystal, Justyna M
Velagapudi, Mohana R
Alonso, Marta M
Zalacain, Marta
Müller, Sabine
Nazarian, Javad
author_sort Ciani, Ludovica
collection PubMed
description Diffuse Midline Gliomas (DMG) are amongst the most lethal pediatric brain tumors. Children diagnosed with DMG face a grim prognosis of 9-11 months from diagnosis. Over 85% of DMG patients harbor mutation affecting histone-encoding genes (H3.1K27M, H3.3K27M) leading to genome hypomethylation and transcriptional disruption. Despite decades of clinical studies, the development of an effective therapy remains a challenge. Triptolide is a diterpenoid triepoxide compound inhibiting cell growth and exhibiting preclinical antitumor activity. A large drug screen conducted by the NCI using DMG cell lines identified triptolide as a candidate for reducing DMG cell viability. To further investigate triptolide and its potential for clinical intervention, we used DMG preclinical in vitro and in vivo models. In vitro viability assays with triptolide alone and in combination with other therapeutic drugs (ONC201 and ONC206), were carried out using seven DMG cell lines. Single treatment with triptolide resulted in a significant decrease in DMG cell viability and combination with both ONC201 and ONC206 showed additivity. Triptolide’s toxicity was assessed in vivo through direct injections into the yolk sac of zebrafish. Preliminary data demonstrated how triptolide has higher toxicity compared to un-injected and DMSO control groups. However, a major limitation of triptolide’s clinical utility is its low solubility. Therefore, for in vivo studies, we used minnelide, a water-soluble analog of triptolide, with potent antitumor properties. Studies were performed in eleven RAG2 female mice. PDX tumor-bearing mice were treated with minnelide and ONC201 for three weeks as single or in combination. Survival studies showed no significance in minnelide monotherapy. However, minnelide + ONC201 combination therapy resulted in significant (p=0.01) survival of PDX models. Our current studies investigate the efficacy of a higher dose of minnelide in vivo. Our goal is to establish minnelide potential as a combination strategy for the treatment of children diagnosed with DMG.
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spelling pubmed-102600952023-06-13 DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA Ciani, Ludovica Laternser, Sandra Kritzer, Bettina Hasler, Kerstin Przystal, Justyna M Velagapudi, Mohana R Alonso, Marta M Zalacain, Marta Müller, Sabine Nazarian, Javad Neuro Oncol Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG Diffuse Midline Gliomas (DMG) are amongst the most lethal pediatric brain tumors. Children diagnosed with DMG face a grim prognosis of 9-11 months from diagnosis. Over 85% of DMG patients harbor mutation affecting histone-encoding genes (H3.1K27M, H3.3K27M) leading to genome hypomethylation and transcriptional disruption. Despite decades of clinical studies, the development of an effective therapy remains a challenge. Triptolide is a diterpenoid triepoxide compound inhibiting cell growth and exhibiting preclinical antitumor activity. A large drug screen conducted by the NCI using DMG cell lines identified triptolide as a candidate for reducing DMG cell viability. To further investigate triptolide and its potential for clinical intervention, we used DMG preclinical in vitro and in vivo models. In vitro viability assays with triptolide alone and in combination with other therapeutic drugs (ONC201 and ONC206), were carried out using seven DMG cell lines. Single treatment with triptolide resulted in a significant decrease in DMG cell viability and combination with both ONC201 and ONC206 showed additivity. Triptolide’s toxicity was assessed in vivo through direct injections into the yolk sac of zebrafish. Preliminary data demonstrated how triptolide has higher toxicity compared to un-injected and DMSO control groups. However, a major limitation of triptolide’s clinical utility is its low solubility. Therefore, for in vivo studies, we used minnelide, a water-soluble analog of triptolide, with potent antitumor properties. Studies were performed in eleven RAG2 female mice. PDX tumor-bearing mice were treated with minnelide and ONC201 for three weeks as single or in combination. Survival studies showed no significance in minnelide monotherapy. However, minnelide + ONC201 combination therapy resulted in significant (p=0.01) survival of PDX models. Our current studies investigate the efficacy of a higher dose of minnelide in vivo. Our goal is to establish minnelide potential as a combination strategy for the treatment of children diagnosed with DMG. Oxford University Press 2023-06-12 /pmc/articles/PMC10260095/ http://dx.doi.org/10.1093/neuonc/noad073.069 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
Ciani, Ludovica
Laternser, Sandra
Kritzer, Bettina
Hasler, Kerstin
Przystal, Justyna M
Velagapudi, Mohana R
Alonso, Marta M
Zalacain, Marta
Müller, Sabine
Nazarian, Javad
DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA
title DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA
title_full DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA
title_fullStr DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA
title_full_unstemmed DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA
title_short DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA
title_sort dipg-22. triptolide as a potentially promising therapy for diffuse midline glioma
topic Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260095/
http://dx.doi.org/10.1093/neuonc/noad073.069
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