[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Golebiewska, Anna; Luxembourg Institute of Health
Hau, Ann-Christin; Luxembourg Institute of Health
Oudin, Anaïs
Stieber, Daniel
Yabo, Yahaya
Baus, Virginie
Barthélémy, Vanessa
Klein, Eliane
Bougnaud, Sébastien
Keunen, Olivier
Wantz, May
Michelucci, Alessandro
Neirinckx, Virginie ; Luxembourg Institute of Health > Department of oncology > NorLux Neuro-Oncology Laboratory
Muller, Arnaud
Kaoma, Tony
Nazarov, Petr
Azuaje, Francisco
De Falco, Alfonso
Flies, Ben
Richart, Lorraine
Poovathingal, Suresh
Arns, Thais
Grzyb, Kamil
Mock, Andreas
Herold-Mende, Christel
Steino, Anne
Brown, Dennis
May, Patrick
Miletic, Hrvoje
Malta, Tathiane
Noushmehr, Houtan
Kwon, Yong-Jun
Jahn, Winnie
Klink, Barbara
Tanner, Georgette
Stead, Lucy
Mittelbronn, Michel
Skupin, Alexander
Hertel, Frank
Bjerkvig, Rolf
Niclou, Simone; Luxembourg Institute of Health > Department of Oncology > NorLux Neuro-oncology laboratory
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