Evaluation von Antagonisten des Wnt-3a-Signalwegs in diffusen großzelligen B-Zell-Lymphomen

Evaluation of Wnt-3a signaling antagonists in diffuse large B-cell lymphomas

by Patricia Take
Doctoral thesis
Date of Examination:2018-11-29
Date of issue:2018-11-26
Advisor:Prof. Dr. Gerald Wulf
Referee:Prof. Dr. Gerald Wulf
Referee:Prof. Dr. Holger Bastians
Persistent Address: http://dx.doi.org/10.53846/goediss-7150

 

 

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Abstract

English

Deregulated activation of Wnt-3a-signaling is a mechanism of intratumoral homeostasis in diffuse large B cell lymphoma (DLBCL). The topic of this study was to evaluate antagonists of this signal pathway for the first time in order to develop strategies for an individually optimized therapy. For the Wnt inhibitors XAV939, IWP-2 and C59, Wnt inhibition in DLBCL cell lines without genetic MYC alterations was shown using a Western blot. Furthermore, for XAV939, a significant inhibition of proliferation and reduction of clonogenicity in vitro were shown, whereas these effects were less demonstrable for C59 and barely measurable for IWP-2. While IWP-2 appears unsuitable for in-vivo studies due to its side-effect profile, C59 qualifies for further investigation due to its effectiveness in the inhibition of clonogenicity. XAV939 affects two tankyrase-dependent processes which are both of interest to cancer therapy: The inhibitor causes suppression of Wnt signaling as well as induction of mitotic arrest and should be studied further as a promising substance. In spite of successful inhibition of Wnt signaling in myocardial tissue, the Wnt inhibiting peptide UM206 appears to have no cytotoxic effect in DLBCL, which is most likely caused by a heterogenous expression pattern of isotypes of the Wnt receptor Frizzled. Based on the description of tumor-suppressive effect by the natural antagonist sFRP4, an innovative strategy for Wnt inhibition in DLBCL was pursued. An immunoconjugate developed in this study from variable parts of anti-CD20 antibodies and sFRP4 specifically attacks tumor cells with stem cell features and could be developed into an effective therapeutic agent for Wnt-regulated DLBCL.
Keywords: Wnt-3a; DLBCL; XAV939; IWP-2; C59; sFRP4; UM206
Schlagwörter: Wnt-3a; DLBCL; XAV939; IWP-2; C59; sFRP4; UM206
 
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