Exploring new treatment strategies for mature T-cell neoplasms based on genetic alterations

by Nicole Schmidt
Doctoral thesis
Date of Examination:2024-04-25
Date of issue:2024-09-10
Advisor:Dr. Raphael Koch
Referee:Dr. Raphael Koch
Referee:Prof. Dr. Holger Bastians
Persistent Address: http://dx.doi.org/10.53846/goediss-10716

 

 

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Abstract

English

Mature T-cell leukemias and lymphomas (mTCL) comprise a heterogeneous group of lymphoid malignancies that are generally associated with poor prognosis, low response to current standard therapy regimes and high relapse rates. New treatment strategies targeting the underlying biology of mTCLs are therefore highly needed to improve patient outcomes. In order to identify potential novel therapeutics, a bioinformatic reporting tool to support treatment decisions was utilized to analyze publicly available genetic data from 1825 mTCL patients covering multiple subtypes. This approach identified potential therapeutics addressing genetic alterations in mTCLs. Based on the knowledge gained with this method, a comprehensive drug screening on genetically and transcriptionally characterized cell lines was performed to assess the in vitro efficacy of potential therapeutics. The analysis revealed in vitro activity of both previously established but also novel therapeutics in mTCL. Notably, various elements within DNA damage response pathways occurred as potential therapeutic targets, most prominently the cell cycle regulator Wee1. Indeed, inhibition of this kinase showed a broad cytotoxic effect in the tested cell lines through abrogation of cell cycle checkpoints, induction of replication stress and premature mitotic entry. Combination strategies enhanced the anti-cancer effect of Wee1 inhibition, especially combined Wee1 and JAK1/2 inhibition increased cytotoxicity in cell lines harboring constitutive STAT3 activation. The synergistic effect seems to be due to increased replication stress through Wee1 inhibition and simultaneous impairment of repair mechanisms and stress responses through JAK1/2 inhibition. Furthermore, the investigated treatment strategy was shown to alter apoptotic dependencies and increase apoptotic priming of mTCL cells. Together, these effects lead to synthetic lethality. Importantly, combined Wee1 and JAK1/2 inhibition showed broad ex vivo activity in primary T-cell prolymphocytic leukemia (T-PLL) patient samples. In summary, this study identified potential molecularly matched therapeutics in mTCL, distinct vulnerabilities within DNA damage response pathways and combinatorial effects of Wee1 and JAK/STAT inhibition in genetically defined subtypes of mTCL and provides a rationale for clinical testing.
Keywords: T-cell lymphomas; WEE1; JAK STAT; Genetic alterations; Targeted therapy; DNA damage response; replication stress; molecular tumorboard
 
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