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Title:
Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology | Acta Neuropathologica
Description:
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.
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Keywords {🔍}
pubmed, tumor, cell, pdoxs, article, fig, cells, google, scholar, tumors, organoids, cas, supplementary, patient, pdox, glioma, resource, dna, online, egfr, gbm, central, models, cancer, expression, methylation, analysis, gliomas, treatment, samples, genetic, data, gene, human, variants, glioblastoma, brain, molecular, performed, patients, drug, tissue, lines, luxembourg, val, profiles, heterogeneity, table, mice, mutations,
Topics {✒️}
core junior c17/bm/11664971/demics g-cimp-low subtype dominated single-cell rna-seq analysis live/dead double labeling article download pdf patient-derived short-term cultures live/dead assay kit additional mdm4/egfrδ25-27-amplified clone endogenous idh1-mutant glioma low-throughput preclinical assays patient-derived xenografts reflects patient-derived xenograft experiments genome-wide dna methylation drop-seq master template wild-type idh1 allele patient-derived cancer xenografts neural stem/progenitor cultures patient-derived orthotopic xenografts central nervous system high-throughput drug testing o-6-methylguanine-dna methyltransferase single cell rna-seq human-specific anti-lamin egfp-negative tumor cells /ml maxima h-rt dna methylation-based classification high-throughput drug screening recapitulate patient-specific genetic human-specific nestin staining high-throughput drug screens recapitulate tumor-intrinsic genetic cancer genome atlas patient-derived tumor xenografts myelin removal beads ii idh-mutant astrocytic gliomas mgmt promoter-unmethylated gbms wilcoxon signed-rank test inherent low-throughput nature kaplan–meier survival curves recruiting host-derived tme pdox-derived organoids appears patient-derived tumour xenografts pdox-derived organoids recapitulate lost wild-type idh1 alfonso de falco idh-mutant lower-grade isopentane flash-frozen tissues clinically-relevant responses c-terminal domain idh1/2mut astrocytomas show
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headline:Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
description: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.
datePublished:2020-10-03T00:00:00Z
dateModified:2020-10-03T00:00:00Z
pageStart:919
pageEnd:949
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keywords:
Glioma
Glioblastoma
Glioma recurrence
Patient-derived orthotopic xenograft
Organoid
Preclinical models
Precision medicine
IDH1
MGMT
VAL-083
Pathology
Neurosciences
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headline:Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
description: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.
datePublished:2020-10-03T00:00:00Z
dateModified:2020-10-03T00:00:00Z
pageStart:919
pageEnd:949
license:http://creativecommons.org/licenses/by/4.0/
sameAs:https://doi.org/10.1007/s00401-020-02226-7
keywords:
Glioma
Glioblastoma
Glioma recurrence
Patient-derived orthotopic xenograft
Organoid
Preclinical models
Precision medicine
IDH1
MGMT
VAL-083
Pathology
Neurosciences
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affiliation:
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name:NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
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name:Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
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name:National Center of Pathology, Laboratoire National de Santé, Dudelange, Luxembourg
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name:Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
name:Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
name:Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
name:Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
name:Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany
name:German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany
name:German Cancer Consortium (DKTK), Heidelberg, Germany
name:Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
name:DelMar Pharmaceuticals, Inc., Vancouver, Canada
name:DelMar Pharmaceuticals, Inc., Menlo Park, USA
name:DelMar Pharmaceuticals, Inc., Vancouver, Canada
name:DelMar Pharmaceuticals, Inc., Menlo Park, USA
name:Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
name:Department of Biomedicine, University of Bergen, Bergen, Norway
name:Department of Pathology, Haukeland University Hospital, Bergen, Norway
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name:Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
name:German Cancer Consortium (DKTK), Dresden, Germany
name:Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden, Germany
name:National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg
name:Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
name:German Cancer Consortium (DKTK), Dresden, Germany
name:Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Dresden, Germany
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name:Leeds Institute of Medical Research at St James’s, St James’s University Hospital, Leeds, UK
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name:NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
name:Department of Biomedicine, University of Bergen, Bergen, Norway
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