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

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 RichartSuresh 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*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)919-949
Number of pages31
JournalActa Neuropathologica
Volume140
Issue number6
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Glioblastoma
  • Glioma
  • Glioma recurrence
  • IDH1
  • MGMT
  • Organoid
  • Patient-derived orthotopic xenograft
  • Precision medicine
  • Preclinical models
  • VAL-083

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