TY - JOUR
T1 - Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
AU - Golebiewska, Anna
AU - Hau, Ann Christin
AU - Oudin, Anaïs
AU - Stieber, Daniel
AU - Yabo, Yahaya A.
AU - Baus, Virginie
AU - Barthelemy, Vanessa
AU - Klein, Eliane
AU - Bougnaud, Sébastien
AU - Keunen, Olivier
AU - Wantz, May
AU - Michelucci, Alessandro
AU - Neirinckx, Virginie
AU - Muller, Arnaud
AU - Kaoma, Tony
AU - Nazarov, Petr V.
AU - Azuaje, Francisco
AU - De Falco, Alfonso
AU - Flies, Ben
AU - Richart, Lorraine
AU - Poovathingal, Suresh
AU - Arns, Thais
AU - Grzyb, Kamil
AU - Mock, Andreas
AU - Herold-Mende, Christel
AU - Steino, Anne
AU - Brown, Dennis
AU - May, Patrick
AU - Miletic, Hrvoje
AU - Malta, Tathiane M.
AU - Noushmehr, Houtan
AU - Kwon, Yong Jun
AU - Jahn, Winnie
AU - Klink, Barbara
AU - Tanner, Georgette
AU - Stead, Lucy F.
AU - Mittelbronn, Michel
AU - Skupin, Alexander
AU - Hertel, Frank
AU - Bjerkvig, Rolf
AU - Niclou, Simone P.
N1 - Funding Information:
We are grateful to the Clinical and Epidemiological Investigation Center (CIEC) of the LIH for support in tumor collection, and to Jean-Jacques Gerardy and Nathalie Nicot for technical assistance. We thank the Helmholtz Zentrum München (Research Unit of Molecular Epidemiology/Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany) for processing the EPIC DNA methylation arrays. We acknowledge the financial support by the Luxembourg Institute of Health, Télévie-FNRS (Grants TETHER n°7.4632.17 and n°7.4615.18), Fondation Cancer Luxembourg (Pan-RTK Targeting), the Luxembourg National Research Fund (FNR; CORE Junior C17/BM/11664971/DEMICS, AFR/14206478 TregBar, INTER/DFG/17/11583046 MechEPI) and the GLIOTRAIN ITN funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 766069 (The material presented and views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out). MM would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant).
Funding Information:
D Brown is CSO at Delmar Pharmaceuticals, A. Steino was preclinical study manager at Delmar Pharmaceuticals. A Golebiewska and S.P. Niclou received a research grant from Delmar Pharmaceuticals. No potential conflict of interest was disclosed by other authors.
Funding Information:
We are grateful to the Clinical and Epidemiological Investigation Center (CIEC) of the LIH for support in tumor collection, and to Jean-Jacques Gerardy and Nathalie Nicot for technical assistance. We thank the Helmholtz Zentrum M?nchen (Research Unit of Molecular Epidemiology/Institute of Epidemiology, German Research Center for Environmental Health, Neuherberg, Germany) for processing the EPIC DNA methylation arrays. We acknowledge the financial support by the Luxembourg Institute of Health, T?l?vie-FNRS (Grants TETHER n?7.4632.17 and n?7.4615.18), Fondation Cancer Luxembourg (Pan-RTK Targeting), the Luxembourg National Research Fund (FNR; CORE Junior C17/BM/11664971/DEMICS,?AFR/14206478 TregBar, INTER/DFG/17/11583046 MechEPI) and the GLIOTRAIN ITN funded by the European Union?s Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No 766069 (The material presented and views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out). MM would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - Glioblastoma
KW - Glioma
KW - Glioma recurrence
KW - IDH1
KW - MGMT
KW - Organoid
KW - Patient-derived orthotopic xenograft
KW - Precision medicine
KW - Preclinical models
KW - VAL-083
UR - http://www.scopus.com/inward/record.url?scp=85091876218&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/33009951
U2 - 10.1007/s00401-020-02226-7
DO - 10.1007/s00401-020-02226-7
M3 - Article
C2 - 33009951
AN - SCOPUS:85091876218
SN - 0001-6322
VL - 140
SP - 919
EP - 949
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -