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http://dx.doi.org/10.18419/opus-13244
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DC Element | Wert | Sprache |
---|---|---|
dc.contributor.author | Vetma, Vesna | - |
dc.contributor.author | Guttà, Cristiano | - |
dc.contributor.author | Peters, Nathalie | - |
dc.contributor.author | Praetorius, Christian | - |
dc.contributor.author | Hutt, Meike | - |
dc.contributor.author | Seifert, Oliver | - |
dc.contributor.author | Meier, Friedegund | - |
dc.contributor.author | Kontermann, Roland | - |
dc.contributor.author | Kulms, Dagmar | - |
dc.contributor.author | Rehm, Markus | - |
dc.date.accessioned | 2023-06-28T08:35:10Z | - |
dc.date.available | 2023-06-28T08:35:10Z | - |
dc.date.issued | 2020 | de |
dc.identifier.issn | 1350-9047 | - |
dc.identifier.issn | 1476-5403 | - |
dc.identifier.other | 1852778458 | - |
dc.identifier.uri | http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-132635 | de |
dc.identifier.uri | http://elib.uni-stuttgart.de/handle/11682/13263 | - |
dc.identifier.uri | http://dx.doi.org/10.18419/opus-13244 | - |
dc.description.abstract | Second generation TRAIL-based therapeutics, combined with sensitising co-treatments, have recently entered clinical trials. However, reliable response predictors for optimal patient selection are not yet available. Here, we demonstrate that a novel and translationally relevant hexavalent TRAIL receptor agonist, IZI1551, in combination with Birinapant, a clinically tested IAP antagonist, efficiently induces cell death in various melanoma models, and that responsiveness can be predicted by combining pathway analysis, data-driven modelling and pattern recognition. Across a panel of 16 melanoma cell lines, responsiveness to IZI1551/Birinapant was heterogeneous, with complete resistance and pronounced synergies observed. Expression patterns of TRAIL pathway regulators allowed us to develop a combinatorial marker that predicts potent cell killing with high accuracy. IZI1551/Birinapant responsiveness could be predicted not only for cell lines, but also for 3D tumour cell spheroids and for cells directly isolated from patient melanoma metastases (80-100% prediction accuracies). Mathematical parameter reduction identified 11 proteins crucial to ensure prediction accuracy, with x-linked inhibitor of apoptosis protein (XIAP) and procaspase-3 scoring highest, and Bcl-2 family members strongly represented. Applied to expression data of a cohort of n = 365 metastatic melanoma patients in a proof of concept in silico trial, the predictor suggested that IZI1551/Birinapant responsiveness could be expected for up to 30% of patient tumours. Overall, response frequencies in melanoma models were very encouraging, and the capability to predict melanoma sensitivity to combinations of latest generation TRAIL-based therapeutics and IAP antagonists can address the need for patient selection strategies in clinical trials based on these novel drugs. | en |
dc.description.sponsorship | European Union’s Horizon 2020 research and innovation programme | de |
dc.description.sponsorship | Deutsche Forschungsgemeinschaft | de |
dc.description.sponsorship | Health Research Board Ireland | de |
dc.description.sponsorship | Projekt DEAL | de |
dc.language.iso | en | de |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/642295 | de |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/766069 | de |
dc.relation.uri | doi:10.1038/s41418-020-0512-5 | de |
dc.rights | info:eu-repo/semantics/openAccess | de |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | de |
dc.subject.ddc | 570 | de |
dc.subject.ddc | 610 | de |
dc.title | Convergence of pathway analysis and pattern recognition predicts sensitization to latest generation TRAIL therapeutics by IAP antagonism | en |
dc.type | article | de |
dc.date.updated | 2023-05-16T02:23:28Z | - |
ubs.fakultaet | Energie-, Verfahrens- und Biotechnik | de |
ubs.fakultaet | Fakultäts- und hochschulübergreifende Einrichtungen | de |
ubs.fakultaet | Fakultätsübergreifend / Sonstige Einrichtung | de |
ubs.institut | Institut für Zellbiologie und Immunologie | de |
ubs.institut | Stuttgart Research Center Systems Biology (SRCSB) | de |
ubs.institut | Stuttgarter Zentrum für Simulationswissenschaften (SC SimTech) | de |
ubs.institut | Fakultätsübergreifend / Sonstige Einrichtung | de |
ubs.publikation.seiten | 2417-2432 | de |
ubs.publikation.source | Cell death & differentiation 27 (2020), S. 2417-2432 | de |
ubs.publikation.typ | Zeitschriftenartikel | de |
Enthalten in den Sammlungen: | 04 Fakultät Energie-, Verfahrens- und Biotechnik |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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s41418-020-0512-5.pdf | 5,54 MB | Adobe PDF | Öffnen/Anzeigen |
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