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HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA

Diffuse hemispheric H3 G34R/V mutant gliomas (G34R/V DHG) are lethal brain malignancies occurring in the cerebral hemisphere of adolescent patients with no effective treatment options. To date, standard care is adapted from adult treatment protocols which include maximal tumor resection, radiotherap...

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Autores principales: Haase, Rebecca, Green, Adam, Kilburn, Lindsay, Filbin, Mariella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260068/
http://dx.doi.org/10.1093/neuonc/noad073.174
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author Haase, Rebecca
Green, Adam
Kilburn, Lindsay
Filbin, Mariella
author_facet Haase, Rebecca
Green, Adam
Kilburn, Lindsay
Filbin, Mariella
author_sort Haase, Rebecca
collection PubMed
description Diffuse hemispheric H3 G34R/V mutant gliomas (G34R/V DHG) are lethal brain malignancies occurring in the cerebral hemisphere of adolescent patients with no effective treatment options. To date, standard care is adapted from adult treatment protocols which include maximal tumor resection, radiotherapy, and chemotherapy with temozolomide (TMZ). In a recent study led by the Children’s Oncology Group (COG, ACNS0423), the combination of the alkylators TMZ and lomustine (CCNU) showed improved event-free survival for pediatric high-grade glioma patients. Still, patient benefits remain limited and thus demand further improvement of treatment protocols. Therefore, the aim of this study is to identify FDA-approved blood-brain-barrier crossing compounds that specifically targeting known vulnerabilities of pediatric high-grade glioma that achieve synergistic treatment results when combined with the double alkylator approach. We conducted a compound screen in combination with TMZ and CCNU on G34R/V-tumor derived gliomaspheres to identify synergies based on cell viability assays in vitro. We identified three candidate agents - Fimepinostat, trametinib, and avapritinib, which inhibit different key oncogenic targets in pediatric high-grade glioma - Pi3K and histone-deacetylases, MAPKs, and PDGFRA, respectively. Our ongoing in vivo study elaborates the translatability of the identified combinatorial therapies in patient derived G34R/V DHG orthotopic xenograft models. We are comparing different study arms of single agent treatment and double as well as triple combinations of alkylators and the candidate agents. This study will serve to determine (i) treatment efficacy, as measured by tumor growth and survival, (ii) occurring side effects, especially alkylator-induced suppression of platelet counts, and (iii) molecular changes upon different treatments using single cell transcriptomics and immunohistochemistry. In summary, we present valuable pre-clinical data supporting the combination of alkylators with targeted agents as a novel treatment strategy in G34R/V DHG, which might be translated into a promising strategy of a new comparative study based on COG trial ACNS0423.
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spelling pubmed-102600682023-06-13 HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA Haase, Rebecca Green, Adam Kilburn, Lindsay Filbin, Mariella Neuro Oncol Final Category: High Grade Glioma/Gliomatosis Cerebri - HGG Diffuse hemispheric H3 G34R/V mutant gliomas (G34R/V DHG) are lethal brain malignancies occurring in the cerebral hemisphere of adolescent patients with no effective treatment options. To date, standard care is adapted from adult treatment protocols which include maximal tumor resection, radiotherapy, and chemotherapy with temozolomide (TMZ). In a recent study led by the Children’s Oncology Group (COG, ACNS0423), the combination of the alkylators TMZ and lomustine (CCNU) showed improved event-free survival for pediatric high-grade glioma patients. Still, patient benefits remain limited and thus demand further improvement of treatment protocols. Therefore, the aim of this study is to identify FDA-approved blood-brain-barrier crossing compounds that specifically targeting known vulnerabilities of pediatric high-grade glioma that achieve synergistic treatment results when combined with the double alkylator approach. We conducted a compound screen in combination with TMZ and CCNU on G34R/V-tumor derived gliomaspheres to identify synergies based on cell viability assays in vitro. We identified three candidate agents - Fimepinostat, trametinib, and avapritinib, which inhibit different key oncogenic targets in pediatric high-grade glioma - Pi3K and histone-deacetylases, MAPKs, and PDGFRA, respectively. Our ongoing in vivo study elaborates the translatability of the identified combinatorial therapies in patient derived G34R/V DHG orthotopic xenograft models. We are comparing different study arms of single agent treatment and double as well as triple combinations of alkylators and the candidate agents. This study will serve to determine (i) treatment efficacy, as measured by tumor growth and survival, (ii) occurring side effects, especially alkylator-induced suppression of platelet counts, and (iii) molecular changes upon different treatments using single cell transcriptomics and immunohistochemistry. In summary, we present valuable pre-clinical data supporting the combination of alkylators with targeted agents as a novel treatment strategy in G34R/V DHG, which might be translated into a promising strategy of a new comparative study based on COG trial ACNS0423. Oxford University Press 2023-06-12 /pmc/articles/PMC10260068/ http://dx.doi.org/10.1093/neuonc/noad073.174 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: High Grade Glioma/Gliomatosis Cerebri - HGG
Haase, Rebecca
Green, Adam
Kilburn, Lindsay
Filbin, Mariella
HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA
title HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA
title_full HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA
title_fullStr HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA
title_full_unstemmed HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA
title_short HGG-25. TARGETED DRUGS SYNERGIZE WITH DOUBLE ALKYLATOR THERAPY IN H3.3 G34R/V PEDIATRIC HIGH-GRADE GLIOMA
title_sort hgg-25. targeted drugs synergize with double alkylator therapy in h3.3 g34r/v pediatric high-grade glioma
topic Final Category: High Grade Glioma/Gliomatosis Cerebri - HGG
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260068/
http://dx.doi.org/10.1093/neuonc/noad073.174
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