Purpose: The Hedgehog-signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened (SMO) and, based on molecular data, may prevent resistance to EGFR targeting.
Methods: To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation. Colony formation (CF) of primary HNSCC cells was studied utilizing the FLAVINO-protocol. Combinatory effects were analysed regarding antagonism, additivity or synergism. Associations between the ex vivo detected mode of action of vismodegib with other treatments related to patient characteristics were assessed and progression-free survival (PFS) in patient groups compared using Kaplan-Meier curves.
Results: Vismodegib suppressed BrdU incorporation significantly stronger than MTT turnover; CF was significantly inhibited at ≥20 µM vismodegib while concentrations <20 µM acted hormetic. Combining 20 µM vismodegib plus docetaxel (T), cisplatin (P), and cetuximab (E), additively enhanced antitumoral activity in HNSCC samples from patients with superior PFS highlighting a potential role for ex-vivo testing of this combination for use as a prognostic classifier. Conclusion: We provide ex-vivo evidence for vismodegib’s potential in HNSCC therapies especially if combined with cetuximab, cisplatin and docetaxel.:Abkürzungsverzeichnis
1 Einleitung
1.1 Kopf-Hals-Tumore
1.1.1 Therapie von Kopf-Hals-TumoreN
1.1.2 Limitationen der etablierten Therapien
1.2 Eingesetzte Chemotherapeutika
1.2.1 Cisplatin
1.2.2 Docetaxel
1.2.3 Cetuximab
1.3 Hedgehog-Signaltransduktionsweg
1.3.1 Hedgehog-Signalweg und Karzinogenese
1.3.2 Vermittlung von Tumortherapieresistenz durch den Hedgehog-Signalweg
1.3.3 Zielgerichtete Tumortherapie durch Blockade des Hedgehog-Signalweges
1.4 Vismodegib
1.5 Ex-Vivo-Chemoresponse-Testung mittels FLAVINO-Assay
1.6 Zusammenfassung der Rationale der Untersuchung
1.7 Aufgabenstellung der Promotionsarbeit
2 Publikation
2.1 Reduzierte Proliferation und Koloniebildung von Plattenepithelkarzinomen der Kopf Hals Region unter dualer Inhibition des EGFR- und Hedgehog-Signalweges
3 Zusammenfassung der Arbeit
4 Literaturverzeichnis
5 Anlagen
5.1 Darstellung des Eigenanteils
5.2 Erklärung über die eigenständige Abfassung der Arbeit
5.3 Lebenslauf
5.4 Publikationen
5.5 Danksagung
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:87228 |
| Date | 28 September 2023 |
| Creators | Liebig, Hannes |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | German |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.1038/nrm3598, 10.1016/j.tips.2009.03.007, 10.1002/hed.21958, 10.1159/000350322, 23749890, 10.1186/s12885-017-3286-5 |
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