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

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, includi...
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Autor*in:	Golebiewska, Anna [verfasserIn] Hau, Ann-Christin [verfasserIn] Oudin, Anaïs [verfasserIn] Stieber, Daniel [verfasserIn] Yabo, Yahaya A. [verfasserIn] Baus, Virginie [verfasserIn] Barthelemy, Vanessa [verfasserIn] Klein, Eliane [verfasserIn] Bougnaud, Sébastien [verfasserIn] Keunen, Olivier [verfasserIn] Wantz, May [verfasserIn] Michelucci, Alessandro [verfasserIn] Neirinckx, Virginie [verfasserIn] Muller, Arnaud [verfasserIn] Kaoma, Tony [verfasserIn] Nazarov, Petr V. [verfasserIn] Azuaje, Francisco [verfasserIn] De Falco, Alfonso [verfasserIn] Flies, Ben [verfasserIn] Richart, Lorraine [verfasserIn] Poovathingal, Suresh [verfasserIn] Arns, Thais [verfasserIn] Grzyb, Kamil [verfasserIn] Mock, Andreas [verfasserIn] Herold-Mende, Christel [verfasserIn] Steino, Anne [verfasserIn] Brown, Dennis [verfasserIn] May, Patrick [verfasserIn] Miletic, Hrvoje [verfasserIn] Malta, Tathiane M. [verfasserIn] Noushmehr, Houtan [verfasserIn] Kwon, Yong-Jun [verfasserIn] Jahn, Winnie [verfasserIn] Klink, Barbara [verfasserIn] Tanner, Georgette [verfasserIn] Stead, Lucy F. [verfasserIn] Mittelbronn, Michel [verfasserIn] Skupin, Alexander [verfasserIn] Hertel, Frank [verfasserIn] Bjerkvig, Rolf [verfasserIn] Niclou, Simone P. [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

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

Übergeordnetes Werk:	Enthalten in: Acta neuropathologica - Berlin : Springer, 1961, 140(2020), 6 vom: 03. Okt., Seite 919-949
Übergeordnetes Werk:	volume:140 ; year:2020 ; number:6 ; day:03 ; month:10 ; pages:919-949

Links:	Volltext

DOI / URN:	10.1007/s00401-020-02226-7

Katalog-ID:	SPR041979575

Internformat


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520			\|a 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.
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700	1		\|a Nazarov, Petr V. \|e verfasserin \|4 aut
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700	1		\|a De Falco, Alfonso \|e verfasserin \|4 aut
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700	1		\|a Brown, Dennis \|e verfasserin \|4 aut
700	1		\|a May, Patrick \|e verfasserin \|4 aut
700	1		\|a Miletic, Hrvoje \|e verfasserin \|4 aut
700	1		\|a Malta, Tathiane M. \|e verfasserin \|4 aut
700	1		\|a Noushmehr, Houtan \|e verfasserin \|4 aut
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700	1		\|a Bjerkvig, Rolf \|e verfasserin \|4 aut
700	1		\|a Niclou, Simone P. \|e verfasserin \|4 aut
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allfields	10.1007/s00401-020-02226-7 doi (DE-627)SPR041979575 (SPR)s00401-020-02226-7-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Golebiewska, Anna verfasserin aut Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Glioma (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Glioma recurrence (dpeaa)DE-He213 Patient-derived orthotopic xenograft (dpeaa)DE-He213 Organoid (dpeaa)DE-He213 Preclinical models (dpeaa)DE-He213 Precision medicine (dpeaa)DE-He213 IDH1 (dpeaa)DE-He213 MGMT (dpeaa)DE-He213 VAL-083 (dpeaa)DE-He213 Hau, Ann-Christin verfasserin aut Oudin, Anaïs verfasserin aut Stieber, Daniel verfasserin aut Yabo, Yahaya A. verfasserin aut Baus, Virginie verfasserin aut Barthelemy, Vanessa verfasserin aut Klein, Eliane verfasserin aut Bougnaud, Sébastien verfasserin aut Keunen, Olivier verfasserin aut Wantz, May verfasserin aut Michelucci, Alessandro verfasserin aut Neirinckx, Virginie verfasserin aut Muller, Arnaud verfasserin aut Kaoma, Tony verfasserin aut Nazarov, Petr V. verfasserin aut Azuaje, Francisco verfasserin aut De Falco, Alfonso verfasserin aut Flies, Ben verfasserin aut Richart, Lorraine verfasserin aut Poovathingal, Suresh verfasserin aut Arns, Thais verfasserin aut Grzyb, Kamil verfasserin aut Mock, Andreas verfasserin aut Herold-Mende, Christel verfasserin aut Steino, Anne verfasserin aut Brown, Dennis verfasserin aut May, Patrick verfasserin aut Miletic, Hrvoje verfasserin aut Malta, Tathiane M. verfasserin aut Noushmehr, Houtan verfasserin aut Kwon, Yong-Jun verfasserin aut Jahn, Winnie verfasserin aut Klink, Barbara verfasserin aut Tanner, Georgette verfasserin aut Stead, Lucy F. verfasserin aut Mittelbronn, Michel verfasserin aut Skupin, Alexander verfasserin aut Hertel, Frank verfasserin aut Bjerkvig, Rolf verfasserin aut Niclou, Simone P. verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 140(2020), 6 vom: 03. Okt., Seite 919-949 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:140 year:2020 number:6 day:03 month:10 pages:919-949 https://dx.doi.org/10.1007/s00401-020-02226-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 140 2020 6 03 10 919-949
spelling	10.1007/s00401-020-02226-7 doi (DE-627)SPR041979575 (SPR)s00401-020-02226-7-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Golebiewska, Anna verfasserin aut Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Glioma (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Glioma recurrence (dpeaa)DE-He213 Patient-derived orthotopic xenograft (dpeaa)DE-He213 Organoid (dpeaa)DE-He213 Preclinical models (dpeaa)DE-He213 Precision medicine (dpeaa)DE-He213 IDH1 (dpeaa)DE-He213 MGMT (dpeaa)DE-He213 VAL-083 (dpeaa)DE-He213 Hau, Ann-Christin verfasserin aut Oudin, Anaïs verfasserin aut Stieber, Daniel verfasserin aut Yabo, Yahaya A. verfasserin aut Baus, Virginie verfasserin aut Barthelemy, Vanessa verfasserin aut Klein, Eliane verfasserin aut Bougnaud, Sébastien verfasserin aut Keunen, Olivier verfasserin aut Wantz, May verfasserin aut Michelucci, Alessandro verfasserin aut Neirinckx, Virginie verfasserin aut Muller, Arnaud verfasserin aut Kaoma, Tony verfasserin aut Nazarov, Petr V. verfasserin aut Azuaje, Francisco verfasserin aut De Falco, Alfonso verfasserin aut Flies, Ben verfasserin aut Richart, Lorraine verfasserin aut Poovathingal, Suresh verfasserin aut Arns, Thais verfasserin aut Grzyb, Kamil verfasserin aut Mock, Andreas verfasserin aut Herold-Mende, Christel verfasserin aut Steino, Anne verfasserin aut Brown, Dennis verfasserin aut May, Patrick verfasserin aut Miletic, Hrvoje verfasserin aut Malta, Tathiane M. verfasserin aut Noushmehr, Houtan verfasserin aut Kwon, Yong-Jun verfasserin aut Jahn, Winnie verfasserin aut Klink, Barbara verfasserin aut Tanner, Georgette verfasserin aut Stead, Lucy F. verfasserin aut Mittelbronn, Michel verfasserin aut Skupin, Alexander verfasserin aut Hertel, Frank verfasserin aut Bjerkvig, Rolf verfasserin aut Niclou, Simone P. verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 140(2020), 6 vom: 03. Okt., Seite 919-949 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:140 year:2020 number:6 day:03 month:10 pages:919-949 https://dx.doi.org/10.1007/s00401-020-02226-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 140 2020 6 03 10 919-949
allfields_unstemmed	10.1007/s00401-020-02226-7 doi (DE-627)SPR041979575 (SPR)s00401-020-02226-7-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Golebiewska, Anna verfasserin aut Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Glioma (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Glioma recurrence (dpeaa)DE-He213 Patient-derived orthotopic xenograft (dpeaa)DE-He213 Organoid (dpeaa)DE-He213 Preclinical models (dpeaa)DE-He213 Precision medicine (dpeaa)DE-He213 IDH1 (dpeaa)DE-He213 MGMT (dpeaa)DE-He213 VAL-083 (dpeaa)DE-He213 Hau, Ann-Christin verfasserin aut Oudin, Anaïs verfasserin aut Stieber, Daniel verfasserin aut Yabo, Yahaya A. verfasserin aut Baus, Virginie verfasserin aut Barthelemy, Vanessa verfasserin aut Klein, Eliane verfasserin aut Bougnaud, Sébastien verfasserin aut Keunen, Olivier verfasserin aut Wantz, May verfasserin aut Michelucci, Alessandro verfasserin aut Neirinckx, Virginie verfasserin aut Muller, Arnaud verfasserin aut Kaoma, Tony verfasserin aut Nazarov, Petr V. verfasserin aut Azuaje, Francisco verfasserin aut De Falco, Alfonso verfasserin aut Flies, Ben verfasserin aut Richart, Lorraine verfasserin aut Poovathingal, Suresh verfasserin aut Arns, Thais verfasserin aut Grzyb, Kamil verfasserin aut Mock, Andreas verfasserin aut Herold-Mende, Christel verfasserin aut Steino, Anne verfasserin aut Brown, Dennis verfasserin aut May, Patrick verfasserin aut Miletic, Hrvoje verfasserin aut Malta, Tathiane M. verfasserin aut Noushmehr, Houtan verfasserin aut Kwon, Yong-Jun verfasserin aut Jahn, Winnie verfasserin aut Klink, Barbara verfasserin aut Tanner, Georgette verfasserin aut Stead, Lucy F. verfasserin aut Mittelbronn, Michel verfasserin aut Skupin, Alexander verfasserin aut Hertel, Frank verfasserin aut Bjerkvig, Rolf verfasserin aut Niclou, Simone P. verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 140(2020), 6 vom: 03. Okt., Seite 919-949 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:140 year:2020 number:6 day:03 month:10 pages:919-949 https://dx.doi.org/10.1007/s00401-020-02226-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 140 2020 6 03 10 919-949
allfieldsGer	10.1007/s00401-020-02226-7 doi (DE-627)SPR041979575 (SPR)s00401-020-02226-7-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Golebiewska, Anna verfasserin aut Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Glioma (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Glioma recurrence (dpeaa)DE-He213 Patient-derived orthotopic xenograft (dpeaa)DE-He213 Organoid (dpeaa)DE-He213 Preclinical models (dpeaa)DE-He213 Precision medicine (dpeaa)DE-He213 IDH1 (dpeaa)DE-He213 MGMT (dpeaa)DE-He213 VAL-083 (dpeaa)DE-He213 Hau, Ann-Christin verfasserin aut Oudin, Anaïs verfasserin aut Stieber, Daniel verfasserin aut Yabo, Yahaya A. verfasserin aut Baus, Virginie verfasserin aut Barthelemy, Vanessa verfasserin aut Klein, Eliane verfasserin aut Bougnaud, Sébastien verfasserin aut Keunen, Olivier verfasserin aut Wantz, May verfasserin aut Michelucci, Alessandro verfasserin aut Neirinckx, Virginie verfasserin aut Muller, Arnaud verfasserin aut Kaoma, Tony verfasserin aut Nazarov, Petr V. verfasserin aut Azuaje, Francisco verfasserin aut De Falco, Alfonso verfasserin aut Flies, Ben verfasserin aut Richart, Lorraine verfasserin aut Poovathingal, Suresh verfasserin aut Arns, Thais verfasserin aut Grzyb, Kamil verfasserin aut Mock, Andreas verfasserin aut Herold-Mende, Christel verfasserin aut Steino, Anne verfasserin aut Brown, Dennis verfasserin aut May, Patrick verfasserin aut Miletic, Hrvoje verfasserin aut Malta, Tathiane M. verfasserin aut Noushmehr, Houtan verfasserin aut Kwon, Yong-Jun verfasserin aut Jahn, Winnie verfasserin aut Klink, Barbara verfasserin aut Tanner, Georgette verfasserin aut Stead, Lucy F. verfasserin aut Mittelbronn, Michel verfasserin aut Skupin, Alexander verfasserin aut Hertel, Frank verfasserin aut Bjerkvig, Rolf verfasserin aut Niclou, Simone P. verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 140(2020), 6 vom: 03. Okt., Seite 919-949 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:140 year:2020 number:6 day:03 month:10 pages:919-949 https://dx.doi.org/10.1007/s00401-020-02226-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 140 2020 6 03 10 919-949
allfieldsSound	10.1007/s00401-020-02226-7 doi (DE-627)SPR041979575 (SPR)s00401-020-02226-7-e DE-627 ger DE-627 rakwb eng 610 ASE 44.90 bkl Golebiewska, Anna verfasserin aut Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Glioma (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Glioma recurrence (dpeaa)DE-He213 Patient-derived orthotopic xenograft (dpeaa)DE-He213 Organoid (dpeaa)DE-He213 Preclinical models (dpeaa)DE-He213 Precision medicine (dpeaa)DE-He213 IDH1 (dpeaa)DE-He213 MGMT (dpeaa)DE-He213 VAL-083 (dpeaa)DE-He213 Hau, Ann-Christin verfasserin aut Oudin, Anaïs verfasserin aut Stieber, Daniel verfasserin aut Yabo, Yahaya A. verfasserin aut Baus, Virginie verfasserin aut Barthelemy, Vanessa verfasserin aut Klein, Eliane verfasserin aut Bougnaud, Sébastien verfasserin aut Keunen, Olivier verfasserin aut Wantz, May verfasserin aut Michelucci, Alessandro verfasserin aut Neirinckx, Virginie verfasserin aut Muller, Arnaud verfasserin aut Kaoma, Tony verfasserin aut Nazarov, Petr V. verfasserin aut Azuaje, Francisco verfasserin aut De Falco, Alfonso verfasserin aut Flies, Ben verfasserin aut Richart, Lorraine verfasserin aut Poovathingal, Suresh verfasserin aut Arns, Thais verfasserin aut Grzyb, Kamil verfasserin aut Mock, Andreas verfasserin aut Herold-Mende, Christel verfasserin aut Steino, Anne verfasserin aut Brown, Dennis verfasserin aut May, Patrick verfasserin aut Miletic, Hrvoje verfasserin aut Malta, Tathiane M. verfasserin aut Noushmehr, Houtan verfasserin aut Kwon, Yong-Jun verfasserin aut Jahn, Winnie verfasserin aut Klink, Barbara verfasserin aut Tanner, Georgette verfasserin aut Stead, Lucy F. verfasserin aut Mittelbronn, Michel verfasserin aut Skupin, Alexander verfasserin aut Hertel, Frank verfasserin aut Bjerkvig, Rolf verfasserin aut Niclou, Simone P. verfasserin aut Enthalten in Acta neuropathologica Berlin : Springer, 1961 140(2020), 6 vom: 03. Okt., Seite 919-949 (DE-627)253389666 (DE-600)1458410-4 1432-0533 nnns volume:140 year:2020 number:6 day:03 month:10 pages:919-949 https://dx.doi.org/10.1007/s00401-020-02226-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 44.90 ASE AR 140 2020 6 03 10 919-949
language	English
source	Enthalten in Acta neuropathologica 140(2020), 6 vom: 03. Okt., Seite 919-949 volume:140 year:2020 number:6 day:03 month:10 pages:919-949
sourceStr	Enthalten in Acta neuropathologica 140(2020), 6 vom: 03. Okt., Seite 919-949 volume:140 year:2020 number:6 day:03 month:10 pages:919-949
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Glioma Glioblastoma Glioma recurrence Patient-derived orthotopic xenograft Organoid Preclinical models Precision medicine IDH1 MGMT VAL-083
dewey-raw	610
isfreeaccess_bool	true
container_title	Acta neuropathologica
authorswithroles_txt_mv	Golebiewska, Anna @@aut@@ Hau, Ann-Christin @@aut@@ Oudin, Anaïs @@aut@@ Stieber, Daniel @@aut@@ Yabo, Yahaya A. @@aut@@ Baus, Virginie @@aut@@ Barthelemy, Vanessa @@aut@@ Klein, Eliane @@aut@@ Bougnaud, Sébastien @@aut@@ Keunen, Olivier @@aut@@ Wantz, May @@aut@@ Michelucci, Alessandro @@aut@@ Neirinckx, Virginie @@aut@@ Muller, Arnaud @@aut@@ Kaoma, Tony @@aut@@ Nazarov, Petr V. @@aut@@ Azuaje, Francisco @@aut@@ De Falco, Alfonso @@aut@@ Flies, Ben @@aut@@ Richart, Lorraine @@aut@@ Poovathingal, Suresh @@aut@@ Arns, Thais @@aut@@ Grzyb, Kamil @@aut@@ Mock, Andreas @@aut@@ Herold-Mende, Christel @@aut@@ Steino, Anne @@aut@@ Brown, Dennis @@aut@@ May, Patrick @@aut@@ Miletic, Hrvoje @@aut@@ Malta, Tathiane M. @@aut@@ Noushmehr, Houtan @@aut@@ Kwon, Yong-Jun @@aut@@ Jahn, Winnie @@aut@@ Klink, Barbara @@aut@@ Tanner, Georgette @@aut@@ Stead, Lucy F. @@aut@@ Mittelbronn, Michel @@aut@@ Skupin, Alexander @@aut@@ Hertel, Frank @@aut@@ Bjerkvig, Rolf @@aut@@ Niclou, Simone P. @@aut@@
publishDateDaySort_date	2020-10-03T00:00:00Z
hierarchy_top_id	253389666
dewey-sort	3610
id	SPR041979575
language_de	englisch
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author	Golebiewska, Anna
spellingShingle	Golebiewska, Anna ddc 610 bkl 44.90 misc Glioma misc Glioblastoma misc Glioma recurrence misc Patient-derived orthotopic xenograft misc Organoid misc Preclinical models misc Precision medicine misc IDH1 misc MGMT misc VAL-083 Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
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topic_title	610 ASE 44.90 bkl Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology Glioma (dpeaa)DE-He213 Glioblastoma (dpeaa)DE-He213 Glioma recurrence (dpeaa)DE-He213 Patient-derived orthotopic xenograft (dpeaa)DE-He213 Organoid (dpeaa)DE-He213 Preclinical models (dpeaa)DE-He213 Precision medicine (dpeaa)DE-He213 IDH1 (dpeaa)DE-He213 MGMT (dpeaa)DE-He213 VAL-083 (dpeaa)DE-He213
topic	ddc 610 bkl 44.90 misc Glioma misc Glioblastoma misc Glioma recurrence misc Patient-derived orthotopic xenograft misc Organoid misc Preclinical models misc Precision medicine misc IDH1 misc MGMT misc VAL-083
topic_unstemmed	ddc 610 bkl 44.90 misc Glioma misc Glioblastoma misc Glioma recurrence misc Patient-derived orthotopic xenograft misc Organoid misc Preclinical models misc Precision medicine misc IDH1 misc MGMT misc VAL-083
topic_browse	ddc 610 bkl 44.90 misc Glioma misc Glioblastoma misc Glioma recurrence misc Patient-derived orthotopic xenograft misc Organoid misc Preclinical models misc Precision medicine misc IDH1 misc MGMT misc VAL-083
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title	Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
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title_full	Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
author_sort	Golebiewska, Anna
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author_browse	Golebiewska, Anna Hau, Ann-Christin Oudin, Anaïs Stieber, Daniel Yabo, Yahaya A. Baus, Virginie Barthelemy, Vanessa Klein, Eliane Bougnaud, Sébastien Keunen, Olivier Wantz, May Michelucci, Alessandro Neirinckx, Virginie Muller, Arnaud Kaoma, Tony Nazarov, Petr V. 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 M. Noushmehr, Houtan Kwon, Yong-Jun Jahn, Winnie Klink, Barbara Tanner, Georgette Stead, Lucy F. Mittelbronn, Michel Skupin, Alexander Hertel, Frank Bjerkvig, Rolf Niclou, Simone P.
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title_sort	patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
title_auth	Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology
url	https://dx.doi.org/10.1007/s00401-020-02226-7
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author2	Hau, Ann-Christin Oudin, Anaïs Stieber, Daniel Yabo, Yahaya A. Baus, Virginie Barthelemy, Vanessa Klein, Eliane Bougnaud, Sébastien Keunen, Olivier Wantz, May Michelucci, Alessandro Neirinckx, Virginie Muller, Arnaud Kaoma, Tony Nazarov, Petr V. 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 M. Noushmehr, Houtan Kwon, Yong-Jun Jahn, Winnie Klink, Barbara Tanner, Georgette Stead, Lucy F. Mittelbronn, Michel Skupin, Alexander Hertel, Frank Bjerkvig, Rolf Niclou, Simone P.
author2Str	Hau, Ann-Christin Oudin, Anaïs Stieber, Daniel Yabo, Yahaya A. Baus, Virginie Barthelemy, Vanessa Klein, Eliane Bougnaud, Sébastien Keunen, Olivier Wantz, May Michelucci, Alessandro Neirinckx, Virginie Muller, Arnaud Kaoma, Tony Nazarov, Petr V. 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 M. Noushmehr, Houtan Kwon, Yong-Jun Jahn, Winnie Klink, Barbara Tanner, Georgette Stead, Lucy F. Mittelbronn, Michel Skupin, Alexander Hertel, Frank Bjerkvig, Rolf Niclou, Simone P.
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doi_str	10.1007/s00401-020-02226-7
up_date	2024-07-04T00:21:07.671Z
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Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

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