Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/35302
Title: IGF2BP1 is the first positive marker for anaplastic thyroid carcinoma and an enhancer of a targetable gene expression signature
Author(s): Haase, JacobLook up in the Integrated Authority File of the German National Library
Referee(s): Hüttelmaier, StefanLook up in the Integrated Authority File of the German National Library
Keßler, SonjaLook up in the Integrated Authority File of the German National Library
König, JulianLook up in the Integrated Authority File of the German National Library
Granting Institution: Martin-Luther-Universität Halle-Wittenberg
Issue Date: 2020
Extent: 1 Online-Ressource (130 Seiten)
Type: HochschulschriftLook up in the Integrated Authority File of the German National Library
Type: Doctoral thesis
Exam Date: 2020-12-11
Language: English
URN: urn:nbn:de:gbv:3:4-1981185920-355121
Abstract: Das anaplastische Schilddrüsenkarzinom (ATC) stellt immer noch eine Ausschlussdiagnose und das Malignom der Schilddrüse dar, welches am häufigsten zum Tode führt. Bisher sind keine Marker für eine eindeutige Diagnose und gezielte Therapien bekannt. Mittels retrospektiver Studie wird in dieser Arbeit das onkofötale IGF2 mRNA-Bindeprotein 1 (IGF2BP1) als erster Marker für das ATC beschrieben, um es eindeutig von anderen Malignomen der Schilddrüse zu unterscheiden. Weiterhin wird durch in vitro- und in vivo-Studien experimentell das onkogene Potenzial von IGF2BP1 als posttranskriptioneller Verstärker MYC-abhängiger Genexpression belegt. Dieser Wirkmechanismus stellt die Grundlage für eine gezielte Therapieoption durch BET-Inhibitoren dar. In vitro-Analysen solcher Inhibitoren untermauern ABBV-075 als hoch effiziente Option für ATC-Therapien dar. Eine Kombination von ABBV-075 mit einem Inhibitor gegen IGF2BP1 (BTYNB) in Synergie stellte sich als noch wirkungsvollere Strategie heraus.
Anaplastic thyroid carcinoma (ATC), still a diagnosis of exclusion, is the most lethal malignancy of the thyroid. Selective markers and drivers remain unknown, inhibiting advances in reliable diagnosis and treatment. In a retrospective study, this thesis unravels that the oncofetal IGF2 mRNA binding protein 1 (IGF2BP1) is the first exclusive marker for ATC, reliably distinguishing from other malignancies of the thyroid. Beyond its marker potential, IGF2BP1 is an oncogenic driver in ATC-derived cells, promoting rapid, invasive growth in vivo and in vitro. IGF2BP1 acts as a post-transcriptional enhancer of MYC-driven gene expression, providing a rationale for effective impairment by BET-inhibitors currently under FDA-evaluation. Comparative analyses of potency and efficacy suggest ABBV-075 as highly efficient first-line treatment option in ATC therapy. A combination of ABBV-075 with direct inhibition of IGF2BP1-function by BTYNB even further proves as a promising treatment strategy with synergistic effect.
URI: https://opendata.uni-halle.de//handle/1981185920/35512
http://dx.doi.org/10.25673/35302
Open Access: Open access publication
License: In Copyright
Appears in Collections:Biowissenschaften; Biologie

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