Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Anna Golebiewska
  • Ann-Christin Hau
  • Anais Oudin
  • Daniel Stieber
  • Yahaya A Yabo
  • Virginie Baus
  • Vanessa Barthelemy
  • Eliane Klein
  • Sebastien Bougnaud
  • Olivier Keunen
  • May Wantz
  • Alessandro Michelucci
  • Virginie Neirinckx
  • Arnaud Muller
  • Tony Kaoma
  • Petr V Nazarov
  • Francisco Azuaje
  • Alfonso De Falco
  • Ben Flies
  • Lorraine Richart
  • Suresh Poovathingal
  • Thais Arns
  • Kamil Grzyb
  • Andreas Mock
  • Christel Herold-Mende
  • Anne Steino
  • Dennis Brown
  • Patrick May
  • Hrvoje Miletic
  • Tathiane M Malta
  • Houtan Noushmehr
  • Yong-Jun Kwon
  • Winnie Jahn
  • Barbara Klink
  • Georgette Tanner
  • Lucy F Stead
  • Michel Mittelbronn
  • Alexander Skupin
  • Frank Hertel
  • Rolf Bjerkvig
  • Simone P Niclou
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000574789000001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1007/s00401-020-02226-7
eISSN
1432-0533
Externe Identifier
  • Clarivate Analytics Document Solution ID: OS2BW
  • PubMed Identifier: 33009951
ISSN
0001-6322
Ausgabe der Veröffentlichung
6
Zeitschrift
ACTA NEUROPATHOLOGICA
Schlüsselwörter
  • Glioma
  • Glioblastoma
  • Glioma recurrence
  • Patient-derived orthotopic xenograft
  • Organoid
  • Preclinical models
  • Precision medicine
  • IDH1
  • MGMT
  • VAL-083
Paginierung
919 - 949
Datum der Veröffentlichung
2020
Status
Published
Titel
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
Sub types
  • Article
Ausgabe der Zeitschrift
140

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
<jats:title>Abstract</jats:title><jats:p>Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in <jats:italic>IDH1</jats:italic>, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in <jats:italic>IDH1</jats:italic>, <jats:italic>ATRX</jats:italic>, <jats:italic>TP53</jats:italic>, <jats:italic>MDM2/4</jats:italic>, amplification of <jats:italic>EGFR</jats:italic>, <jats:italic>PDGFRA</jats:italic>, <jats:italic>MET</jats:italic>, <jats:italic>CDK4/6</jats:italic>, <jats:italic>MDM2/4</jats:italic>, and deletion of <jats:italic>CDKN2A/B</jats:italic>, <jats:italic>PTCH</jats:italic>, and <jats:italic>PTEN</jats:italic>. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to <jats:italic>MGMT</jats:italic> promoter and <jats:italic>EGFR/CDK</jats:italic> status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.</jats:p>
Autoren
  • Anna Golebiewska
  • Ann-Christin Hau
  • Anaïs Oudin
  • Daniel Stieber
  • Yahaya A Yabo
  • Virginie Baus
  • Vanessa Barthelemy
  • Eliane Klein
  • Sébastien Bougnaud
  • Olivier Keunen
  • May Wantz
  • Alessandro Michelucci
  • Virginie Neirinckx
  • Arnaud Muller
  • Tony Kaoma
  • Petr V Nazarov
  • Francisco Azuaje
  • Alfonso De Falco
  • Ben Flies
  • Lorraine Richart
  • Suresh Poovathingal
  • Thais Arns
  • Kamil Grzyb
  • Andreas Mock
  • Christel Herold-Mende
  • Anne Steino
  • Dennis Brown
  • Patrick May
  • Hrvoje Miletic
  • Tathiane M Malta
  • Houtan Noushmehr
  • Yong-Jun Kwon
  • Winnie Jahn
  • Barbara Klink
  • Georgette Tanner
  • Lucy F Stead
  • Michel Mittelbronn
  • Alexander Skupin
  • Frank Hertel
  • Rolf Bjerkvig
  • Simone P Niclou
DOI
10.1007/s00401-020-02226-7
eISSN
1432-0533
ISSN
0001-6322
Ausgabe der Veröffentlichung
6
Zeitschrift
Acta Neuropathologica
Sprache
en
Online publication date
2020
Paginierung
919 - 949
Datum der Veröffentlichung
2020
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1007/s00401-020-02226-7
Datum der Datenerfassung
2021
Titel
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
Ausgabe der Zeitschrift
140

Datenquelle: Crossref

Abstract
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
Addresses
  • NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84, Val Fleuri, 1526, Luxembourg, Luxembourg.
Autoren
  • Anna Golebiewska
  • Ann-Christin Hau
  • Anaïs Oudin
  • Daniel Stieber
  • Yahaya A Yabo
  • Virginie Baus
  • Vanessa Barthelemy
  • Eliane Klein
  • Sébastien Bougnaud
  • Olivier Keunen
  • May Wantz
  • Alessandro Michelucci
  • Virginie Neirinckx
  • Arnaud Muller
  • Tony Kaoma
  • Petr V Nazarov
  • Francisco Azuaje
  • Alfonso De Falco
  • Ben Flies
  • Lorraine Richart
  • Suresh Poovathingal
  • Thais Arns
  • Kamil Grzyb
  • Andreas Mock
  • Christel Herold-Mende
  • Anne Steino
  • Dennis Brown
  • Patrick May
  • Hrvoje Miletic
  • Tathiane M Malta
  • Houtan Noushmehr
  • Yong-Jun Kwon
  • Winnie Jahn
  • Barbara Klink
  • Georgette Tanner
  • Lucy F Stead
  • Michel Mittelbronn
  • Alexander Skupin
  • Frank Hertel
  • Rolf Bjerkvig
  • Simone P Niclou
DOI
10.1007/s00401-020-02226-7
eISSN
1432-0533
Externe Identifier
  • PubMed Identifier: 33009951
  • PubMed Central ID: PMC7666297
Funding acknowledgements
  • Télévie-FNRS: n°7.4615.18
  • H2020 Marie Skłodowska-Curie Actions: 766069
  • Fonds National de la Recherche Luxembourg: PEARL award - P16/BM/11192868
  • Fondation Cancer Luxembourg: Pan-RTK
  • Fonds National de la Recherche Luxembourg: C17/BM/11664971
  • Télévie-FNRS: n°7.4632.17
Open access
true
ISSN
0001-6322
Ausgabe der Veröffentlichung
6
Zeitschrift
Acta neuropathologica
Schlüsselwörter
  • Organoids
  • Animals
  • Humans
  • Mice
  • Rats
  • Glioma
  • Glioblastoma
  • Brain Neoplasms
  • Neoplasm Recurrence, Local
  • Heterografts
  • Precision Medicine
  • Temozolomide
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Open access status
Open Access
Paginierung
919 - 949
Datum der Veröffentlichung
2020
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2020
Titel
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
140

Files

https://link.springer.com/content/pdf/10.1007/s00401-020-02226-7.pdf https://europepmc.org/articles/PMC7666297?pdf=render

Datenquelle: Europe PubMed Central

Abstract
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
Date of acceptance
2020
Autoren
  • Anna Golebiewska
  • Ann-Christin Hau
  • Anaïs Oudin
  • Daniel Stieber
  • Yahaya A Yabo
  • Virginie Baus
  • Vanessa Barthelemy
  • Eliane Klein
  • Sébastien Bougnaud
  • Olivier Keunen
  • May Wantz
  • Alessandro Michelucci
  • Virginie Neirinckx
  • Arnaud Muller
  • Tony Kaoma
  • Petr V Nazarov
  • Francisco Azuaje
  • Alfonso De Falco
  • Ben Flies
  • Lorraine Richart
  • Suresh Poovathingal
  • Thais Arns
  • Kamil Grzyb
  • Andreas Mock
  • Christel Herold-Mende
  • Anne Steino
  • Dennis Brown
  • Patrick May
  • Hrvoje Miletic
  • Tathiane M Malta
  • Houtan Noushmehr
  • Yong-Jun Kwon
  • Winnie Jahn
  • Barbara Klink
  • Georgette Tanner
  • Lucy F Stead
  • Michel Mittelbronn
  • Alexander Skupin
  • Frank Hertel
  • Rolf Bjerkvig
  • Simone P Niclou
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/33009951
DOI
10.1007/s00401-020-02226-7
eISSN
1432-0533
Externe Identifier
  • PubMed Central ID: PMC7666297
Ausgabe der Veröffentlichung
6
Zeitschrift
Acta Neuropathol
Schlüsselwörter
  • Glioblastoma
  • Glioma
  • Glioma recurrence
  • IDH1
  • MGMT
  • Organoid
  • Patient-derived orthotopic xenograft
  • Precision medicine
  • Preclinical models
  • VAL-083
  • Animals
  • Brain Neoplasms
  • Glioblastoma
  • Glioma
  • Heterografts
  • Humans
  • Mice
  • Neoplasm Recurrence, Local
  • Organoids
  • Precision Medicine
  • Rats
  • Temozolomide
Sprache
eng
Country
Germany
Paginierung
919 - 949
PII
10.1007/s00401-020-02226-7
Datum der Veröffentlichung
2020
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
140

Datenquelle: PubMed

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