Funktionelles Apoptose-Profiling zur Weiterentwicklung zielgerichteter Therapien für die adulte T-Zell akute lymphatische Leukämie (T-ALL)

Functional apoptosis profiling for the further development of targeted therapies for adult T-cell acute lymphoblastic leukemia (T-ALL)

by Lara Lissow
Doctoral thesis
Date of Examination:2025-07-08
Date of issue:2025-06-23
Advisor:PD Dr. Raphael Koch
Referee:PD Dr. Raphael Koch
Referee:PD Dr. Alexander König
Persistent Address: http://dx.doi.org/10.53846/goediss-11349

 

 

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Abstract

English

T-cell acute lymphoblastic leukaemia is a very aggressive haematological neoplasia characterised by malignantly transformed precursor T-lymphocytes. Considering the poor prognosis and limited treatment options for affected patients, there is an urgent need to identify and test new treatment options. The growing understanding of the molecular properties of T-ALL cells, in addition to the investigation of apoptotic mechanisms and their therapeutic targets, is a relevant treatment option for patients and is the central topic of this work. To identify potential therapeutics addressing genetic alterations in T-ALL, recently published genetic datasets from patients with T-ALL were analyzed with a bioinformatic approach that systematically queries public databases to report evidence for therapeutics targeting distinct genetic alterations in cancer. This analysis identified several potential therapeutics for T-ALL that were subsequently tested for their cytotoxic activity in T-ALL cell lines. Notably, inhibitors of the PI3K/mTOR pathway showed promising preclinical activity. However, the heterogenity of cellular responses prompted additional experiments dissecting specific effects of PI3K/mTOR inhibitors on the regulation of mitochondrial apoptosis using BH3 profiling. These experiments provided a rationale for drug combination strategies of PI3K/mTOR inhibitors and BH3 mimetics as selective inhibitors of anti-apoptotic BCL-2 family members. Based on these findings, the effects of simultaneous inhibition of the PI3K/mTOR signaling pathway and specific BH3-mimetic were investigated and heterogenous, cell line-specific effects of drug combinations were observed. These results underline the need for a precise, functional characterization of the specific impact of targeted therapeutics on the regulation of mitochondrial apoptosis as a basis for personalized therapeutic strategies incorporating specific BH3-mimetics. Here, dynamic BH3 profiling could be used as an integrative functional tool to establish personalized drug combinations for T-ALL patients.
Keywords: t-all; t-cell acute lymphoblastic leukemia; BH3 profiling; mTOR/PI3K signaling pathway
Schlagwörter: T-ALL; T-Zell akute lymphatische Leukämie; BH3-Profiling; mTOR/PI3K-Signalweg