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MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG

Paediatric high-grade glioma comprise multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived models represent useful tools for mechanistic and preclinical investigations based upon their retention of key genetic/epigenetic features and the...

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Autores principales: Carvalho, Diana, Mackay, Alan, Temelso, Sara, Izquierdo, Elisa, Fernandez, Elisabet Potente, Rogers, Rebecca, Boult, Jessica, Salom, Janat Fazal, Simon, Natalie, Clarke, Matthew, Molinari, Valeria, Kessler, Ketty, Burford, Anna, Bjerke, Lynn, Fofana, Mariama, Hubank, Michael, Pears, Jane, Moore, Andrew, Carcaboso, Angel Montero, Marshall, Lynley, Carceller, Fernando, Robinson, Simon, Hargrave, Darren, Vinci, Maria, Jones, Chris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715119/
http://dx.doi.org/10.1093/neuonc/noaa222.593
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author Carvalho, Diana
Mackay, Alan
Temelso, Sara
Izquierdo, Elisa
Fernandez, Elisabet Potente
Rogers, Rebecca
Boult, Jessica
Salom, Janat Fazal
Simon, Natalie
Clarke, Matthew
Molinari, Valeria
Kessler, Ketty
Burford, Anna
Bjerke, Lynn
Fofana, Mariama
Hubank, Michael
Pears, Jane
Moore, Andrew
Carcaboso, Angel Montero
Marshall, Lynley
Carceller, Fernando
Robinson, Simon
Hargrave, Darren
Vinci, Maria
Jones, Chris
author_facet Carvalho, Diana
Mackay, Alan
Temelso, Sara
Izquierdo, Elisa
Fernandez, Elisabet Potente
Rogers, Rebecca
Boult, Jessica
Salom, Janat Fazal
Simon, Natalie
Clarke, Matthew
Molinari, Valeria
Kessler, Ketty
Burford, Anna
Bjerke, Lynn
Fofana, Mariama
Hubank, Michael
Pears, Jane
Moore, Andrew
Carcaboso, Angel Montero
Marshall, Lynley
Carceller, Fernando
Robinson, Simon
Hargrave, Darren
Vinci, Maria
Jones, Chris
author_sort Carvalho, Diana
collection PubMed
description Paediatric high-grade glioma comprise multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived models represent useful tools for mechanistic and preclinical investigations based upon their retention of key genetic/epigenetic features and their amenability to high-throughput approaches. We have collected ~100 in vitro models representing multiple subtypes (H3.3/H3.2/H3.1K27M, H3.3G34R/V, BRAF, MYCN_amp, NTRK_fusion, hypermutator, others) established under 2D (laminin) and/or 3D (neurosphere) conditions, credentialed by phenotypic (growth, invasion/migration) and molecular (methylation array, DNA sequencing, RNAseq) comparison to the original tumour sample. These were derived from patients at our local hospitals (n=29), as part of national co-clinical trials (n=19), from international collaborating centres (n=11), or shared directly by research groups worldwide (n=45). These have variously been subjected to pharmacological (approved/experimental drug libraries) and/or genetic screening (whole-genome CRISPR) to identify specific biological dependencies. Many have been established as orthotopic xenografts in vivo (PDX), with detailed pathological and radiological correlations with the clinical disease, and with tumorigenic latencies ranging from 48–435 days. This resource has allowed us to identify genotype-specific synthetic lethalities and responses to targeted inhibitors, including olaparib (PARP) with ATRX, nutlin-3 (MDM2) with PPM1D, AZD1775 (WEE1) with TP53, and CYC065 (CDK9) with MYCN-amplification. Combinatorial screening highlighted synergies in ACVR1-mutant DIPG between novel ALK2 inhibitors and ONC201 (DRD2). Rapid screening allows for feedback of drug sensitivities to treating clinicians at relapse, whilst mechanistic underpinning of these interactions and use of the models to identify specific mediators of resistance will allow for rational future trial design.
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spelling pubmed-77151192020-12-09 MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG Carvalho, Diana Mackay, Alan Temelso, Sara Izquierdo, Elisa Fernandez, Elisabet Potente Rogers, Rebecca Boult, Jessica Salom, Janat Fazal Simon, Natalie Clarke, Matthew Molinari, Valeria Kessler, Ketty Burford, Anna Bjerke, Lynn Fofana, Mariama Hubank, Michael Pears, Jane Moore, Andrew Carcaboso, Angel Montero Marshall, Lynley Carceller, Fernando Robinson, Simon Hargrave, Darren Vinci, Maria Jones, Chris Neuro Oncol Preclinical Models/Experimental Therapy/Drug Discovery Paediatric high-grade glioma comprise multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived models represent useful tools for mechanistic and preclinical investigations based upon their retention of key genetic/epigenetic features and their amenability to high-throughput approaches. We have collected ~100 in vitro models representing multiple subtypes (H3.3/H3.2/H3.1K27M, H3.3G34R/V, BRAF, MYCN_amp, NTRK_fusion, hypermutator, others) established under 2D (laminin) and/or 3D (neurosphere) conditions, credentialed by phenotypic (growth, invasion/migration) and molecular (methylation array, DNA sequencing, RNAseq) comparison to the original tumour sample. These were derived from patients at our local hospitals (n=29), as part of national co-clinical trials (n=19), from international collaborating centres (n=11), or shared directly by research groups worldwide (n=45). These have variously been subjected to pharmacological (approved/experimental drug libraries) and/or genetic screening (whole-genome CRISPR) to identify specific biological dependencies. Many have been established as orthotopic xenografts in vivo (PDX), with detailed pathological and radiological correlations with the clinical disease, and with tumorigenic latencies ranging from 48–435 days. This resource has allowed us to identify genotype-specific synthetic lethalities and responses to targeted inhibitors, including olaparib (PARP) with ATRX, nutlin-3 (MDM2) with PPM1D, AZD1775 (WEE1) with TP53, and CYC065 (CDK9) with MYCN-amplification. Combinatorial screening highlighted synergies in ACVR1-mutant DIPG between novel ALK2 inhibitors and ONC201 (DRD2). Rapid screening allows for feedback of drug sensitivities to treating clinicians at relapse, whilst mechanistic underpinning of these interactions and use of the models to identify specific mediators of resistance will allow for rational future trial design. Oxford University Press 2020-12-04 /pmc/articles/PMC7715119/ http://dx.doi.org/10.1093/neuonc/noaa222.593 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 Preclinical Models/Experimental Therapy/Drug Discovery
Carvalho, Diana
Mackay, Alan
Temelso, Sara
Izquierdo, Elisa
Fernandez, Elisabet Potente
Rogers, Rebecca
Boult, Jessica
Salom, Janat Fazal
Simon, Natalie
Clarke, Matthew
Molinari, Valeria
Kessler, Ketty
Burford, Anna
Bjerke, Lynn
Fofana, Mariama
Hubank, Michael
Pears, Jane
Moore, Andrew
Carcaboso, Angel Montero
Marshall, Lynley
Carceller, Fernando
Robinson, Simon
Hargrave, Darren
Vinci, Maria
Jones, Chris
MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG
title MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG
title_full MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG
title_fullStr MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG
title_full_unstemmed MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG
title_short MODL-20. A BIOBANK OF ~100 PATIENT-DERIVED MODELS REPRESENTING BIOLOGICAL HETEROGENEITY AND DISTINCT THERAPEUTIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMA AND DIPG
title_sort modl-20. a biobank of ~100 patient-derived models representing biological heterogeneity and distinct therapeutic dependencies in paediatric high grade glioma and dipg
topic Preclinical Models/Experimental Therapy/Drug Discovery
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715119/
http://dx.doi.org/10.1093/neuonc/noaa222.593
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