Evaluation des oral verfügbaren Smoothened-Antagonisten LDE225 zur Therapie von Inselzelltumoren in der transgenen Rip1Tag2-Maus

Der Hedgehog-Signalweg und sein Rezeptor Smoothened konnten in vorausgegangenen Studien als potenzieller therapeutischer Angriffspunkt bei pankreatischen neuroendokrinen Neoplasien identifiziert werden. Ziel dieser Arbeit war die Evaluation des oral bioverfügbaren Smo-Antagonisten LDE225 als neue Th...

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Bibliographic Details
Main Author: Wiese, Dominik
Contributors: Fendrich, Volker (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2013
Online Access:PDF Full Text
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Recent studies were able to identify the Hedgehog-pathway and its receptor Smoothened as a potential therapeutic target in pancreatic neuroendocrine neoplasms. The goal of this study was to evaluate the orally bioavailable Smo-antagonist LDE225 as a new therapeutic agent. Such an evaluation had not been performed for islet cell tumors. To investigate in vivo effectiveness, Rip1Tag2 transgenic mice were treated from week 5 till death with a dose of 80 mg/kg/d. Resected pancreata from treated and untreated mice were microscopically and immunohistochemically evaluated. Additionally, quantitative real-time-PCR for Hh target genes was performed on cDNA synthesized from isolated islet RNA. Microscopically, the treatment reduced tumor size by 95%. Median survival was significantly prolonged in treated mice (p<0,05). Quantitative real-time-PCR showed a clear downregulation of Hh target genes Gli1, Ptch1 and Hip1, confirming effective pharmacologic levels within the desired tissue site in vivo. The findings of this study suggest that the orally bioavailable Smo-antagonist LDE225 might provide new options in the therapy of pancreatic neuroendocrine neoplasms.