[en] Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.
Research center :
LIH - Luxembourg Institute of Health - Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) - Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Oncology
Author, co-author :
GOLEBIEWSKA, Anna ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC)
Hau, Ann-Christin
Oudin, Anais
Stieber, Daniel
Yabo, Yahaya A.
Baus, Virginie
Barthelemy, Vanessa
Klein, Eliane
Bougnaud, Sebastien
Keunen, Olivier
Wantz, May
MICHELUCCI, Alessandro ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Neirinckx, Virginie
Muller, Arnaud
Kaoma, Tony
Nazarov, Petr V.
AZUAJE, Francisco ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC)
De Falco, Alfonso
Flies, Ben
Richart, Lorraine
Poovathingal, Suresh
ARNS, Thais ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
GRZYB, Kamil ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Mock, Andreas
Herold-Mende, Christel
Steino, Anne
Brown, Dennis
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Miletic, Hrvoje
Malta, Tathiane M.
Noushmehr, Houtan
KWON, Yong-Jun ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Jahn, Winnie
Klink, Barbara
Tanner, Georgette
Stead, Lucy F.
MITTELBRONN, Michel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
SKUPIN, Alexander ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
HERTEL, Frank ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Bjerkvig, Rolf
NICLOU, Simone ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC)
H2020 - 766069 - GLIOTRAIN - Exploiting GLIOblastoma intractability to address European research TRAINing needs in translational brain tumour research, cancer systems medicine and integrative multi-omics
Funders :
Télévie-FNRS (Grants n°7.4632.17, 4615.18) Fondation Cancer Luxembourg (Pan-RTK Targeting) FNR; CORE Junior C17/BM/11664971/DEMICS GLIOTRAIN ITN funded by the European Union’s Horizon 2020 Marie Skłodowska-Curie grant agreement No 766069 FNR PEARL P16/BM/11192868 grant CE - Commission Européenne [BE]