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MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY

Replication repair deficiency (RRD) is the leading cause of hypermutant brain tumours in children. RRD is caused by defects in one of four mismatch repair (MMR) genes and mutations in POLE or POLD1. Such tumours are resistant to common therapeutic agents and animal models are needed to study RRD in...

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Autores principales: Galati, Melissa, Li, Li, Sudhaman, Sumedha, Lipman, Tatiana, Stengs, Lucie, Elshaer, Dana, Bridge, Taylor, Semenova, Dar’ya, Edwards, Melissa, Hodel, Karl, Forster, Victoria J, Nunes, Nuno M, Martin, Alberto, Bouffet, Eric, Pursell, Zachary, Hawkins, Cynthia, Tabori, Uri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715596/
http://dx.doi.org/10.1093/neuonc/noaa222.598
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author Galati, Melissa
Li, Li
Sudhaman, Sumedha
Lipman, Tatiana
Stengs, Lucie
Elshaer, Dana
Bridge, Taylor
Semenova, Dar’ya
Edwards, Melissa
Hodel, Karl
Forster, Victoria J
Nunes, Nuno M
Martin, Alberto
Bouffet, Eric
Pursell, Zachary
Hawkins, Cynthia
Tabori, Uri
author_facet Galati, Melissa
Li, Li
Sudhaman, Sumedha
Lipman, Tatiana
Stengs, Lucie
Elshaer, Dana
Bridge, Taylor
Semenova, Dar’ya
Edwards, Melissa
Hodel, Karl
Forster, Victoria J
Nunes, Nuno M
Martin, Alberto
Bouffet, Eric
Pursell, Zachary
Hawkins, Cynthia
Tabori, Uri
author_sort Galati, Melissa
collection PubMed
description Replication repair deficiency (RRD) is the leading cause of hypermutant brain tumours in children. RRD is caused by defects in one of four mismatch repair (MMR) genes and mutations in POLE or POLD1. Such tumours are resistant to common therapeutic agents and animal models are needed to study RRD in vivo and test novel therapies like immune checkpoint inhibitors (ICIs). To model RRD brain tumours specifically, we engineered a Pole mutant mouse model harbouring the S459F mutation (Pole(S459F)). We combined Pole(S459F) mice with conditional Msh2 knockout (Msh2(LoxP)) and Nestin-cre mice. All Nestin-cre(+)Msh2(LoxP/LoxP)Pole(S459F/+) mice rapidly succumbed to posterior fossa brain tumours between 8.6 and 12.4 weeks. Importantly, tumours exhibited hallmark “ultrahypermutation” (~350 mutations/Mb) and the corresponding signatures characteristic of human combined MMR and POLE-proofreading glioblastoma. Interestingly, Nestin-cre(+)Msh2(LoxP/LoxP)Pole(S459F/S459F) mice failed to establish normal cerebella, suggesting such mutational loads may not support normal brain development. Furthermore, OLIG2-cre(+)Msh2(LoxP/LoxP)Pole(S459F/+) mice failed to develop tumors. Tumors transplanted into syngeneic vs immunocompromised animals egrafted well orthotopically in the mouse hindbrain but significantly less efficiently when engrafted subcutaneously. Furthermore, immunocompromised and subcutaneous tumors revealed striking differences in mutational burden and clonal architecture, suggestive of nonautonomous immunoediting. Finally, anti-PD1 was sufficient to treat subcutaneously engrafted tumors in immunocompetent animals. This first mouse model of immunocompetent, hypermutant brain tumors can be used to uncover unique characteristics of RRD tumour evolution and allow for immune based therapeutic preclinical testing. Experiments to assess combinational ICIs and other therapeutic interventions in orthotopically transplanted tumors will also be presented.
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spelling pubmed-77155962020-12-09 MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY Galati, Melissa Li, Li Sudhaman, Sumedha Lipman, Tatiana Stengs, Lucie Elshaer, Dana Bridge, Taylor Semenova, Dar’ya Edwards, Melissa Hodel, Karl Forster, Victoria J Nunes, Nuno M Martin, Alberto Bouffet, Eric Pursell, Zachary Hawkins, Cynthia Tabori, Uri Neuro Oncol Preclinical Models/Experimental Therapy/Drug Discovery Replication repair deficiency (RRD) is the leading cause of hypermutant brain tumours in children. RRD is caused by defects in one of four mismatch repair (MMR) genes and mutations in POLE or POLD1. Such tumours are resistant to common therapeutic agents and animal models are needed to study RRD in vivo and test novel therapies like immune checkpoint inhibitors (ICIs). To model RRD brain tumours specifically, we engineered a Pole mutant mouse model harbouring the S459F mutation (Pole(S459F)). We combined Pole(S459F) mice with conditional Msh2 knockout (Msh2(LoxP)) and Nestin-cre mice. All Nestin-cre(+)Msh2(LoxP/LoxP)Pole(S459F/+) mice rapidly succumbed to posterior fossa brain tumours between 8.6 and 12.4 weeks. Importantly, tumours exhibited hallmark “ultrahypermutation” (~350 mutations/Mb) and the corresponding signatures characteristic of human combined MMR and POLE-proofreading glioblastoma. Interestingly, Nestin-cre(+)Msh2(LoxP/LoxP)Pole(S459F/S459F) mice failed to establish normal cerebella, suggesting such mutational loads may not support normal brain development. Furthermore, OLIG2-cre(+)Msh2(LoxP/LoxP)Pole(S459F/+) mice failed to develop tumors. Tumors transplanted into syngeneic vs immunocompromised animals egrafted well orthotopically in the mouse hindbrain but significantly less efficiently when engrafted subcutaneously. Furthermore, immunocompromised and subcutaneous tumors revealed striking differences in mutational burden and clonal architecture, suggestive of nonautonomous immunoediting. Finally, anti-PD1 was sufficient to treat subcutaneously engrafted tumors in immunocompetent animals. This first mouse model of immunocompetent, hypermutant brain tumors can be used to uncover unique characteristics of RRD tumour evolution and allow for immune based therapeutic preclinical testing. Experiments to assess combinational ICIs and other therapeutic interventions in orthotopically transplanted tumors will also be presented. Oxford University Press 2020-12-04 /pmc/articles/PMC7715596/ http://dx.doi.org/10.1093/neuonc/noaa222.598 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
Galati, Melissa
Li, Li
Sudhaman, Sumedha
Lipman, Tatiana
Stengs, Lucie
Elshaer, Dana
Bridge, Taylor
Semenova, Dar’ya
Edwards, Melissa
Hodel, Karl
Forster, Victoria J
Nunes, Nuno M
Martin, Alberto
Bouffet, Eric
Pursell, Zachary
Hawkins, Cynthia
Tabori, Uri
MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
title MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
title_full MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
title_fullStr MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
title_full_unstemmed MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
title_short MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
title_sort modl-25. replication repair deficient mouse models provide insight on hypermutant brain tumours, mechanisms of immune evasion, and combinatorial immunotherapy
topic Preclinical Models/Experimental Therapy/Drug Discovery
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715596/
http://dx.doi.org/10.1093/neuonc/noaa222.598
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