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Author: Till, Andreas ×

Publications Search Results

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  • Publication
    A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma
    ( 2023)
    Kebir, Sied
    ;
    Ullrich, Vivien
    ;
    Berger, Pia
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    Dobersalske, Celia
    ;
    Langer, Sarah
    ;
    Rauschenbach, Laurèl
    ;
    Trageser, Daniel
    ;
    Till, Andreas
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    Lorbeer, Franziska K.
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    Wieland, Anja
    ;
    Wilhelm-Buchstab, Timo Martin
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    Ahmad, Ashar
    ;
    Fröhlich, Holger
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    Cima, Igor
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    Prasad, Shruthi
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    Matschke, Johann
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    Jendrossek, V.
    ;
    Remke, Marc
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    Grüner, Barbara M.
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    Roesch, Alexander
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    Siveke, Jens T.
    ;
    Herold-Mende, Christel C.
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    Blau, Tobias
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    Keyvani, Kathy
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    Landeghem, F. van
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    Pietsch, Torsten
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    Felsberg, Jörg U.
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    Reifenberger, Guido
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    Weller, Michael
    ;
    Sure, Ulrich
    ;
    Brüstle, Oliver
    ;
    Simon, Matthias
    ;
    Glas, Martin
    ;
    Scheffler, Björn
    PURPOSE: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. EXPERIMENTAL DESIGN: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. RESULTS: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. CONCLUSIONS: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.
  • Publication
    Drug repositioning of antiretroviral ritonavir for combinatorial therapy in glioblastoma
    ( 2020)
    Rauschenbach, Laurèl
    ;
    Wieland, Anja
    ;
    Reinartz, Roman
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    Kebir, Sied
    ;
    Till, Andreas
    ;
    Darkwah Oppong, Marvin
    ;
    Dobersalske, Celia
    ;
    Ullrich, Vivien
    ;
    Ahmad, Ashar
    ;
    Jabbarli, Ramazan
    ;
    Pierscianek, Daniela
    ;
    Fröhlich, Holger
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    Simon, Matthias
    ;
    Brüstle, Oliver
    ;
    Sure, Ulrich
    ;
    Glas, Martin
    ;
    Scheffler, Björn
    Background The protease inhibitor ritonavir (RTV) is a clinical-stage inhibitor of the human immunodeficiency virus. In a drug repositioning approach, we here exhibit the additional potential of RTV to augment current treatment of glioblastoma, the most aggressive primary brain tumour of adulthood. Methods We explored the antitumour activity of RTV and mechanisms of action in a broad spectrum of short-term expanded clinical cell samples from primary and recurrent glioblastoma and in a cohort of conventional cell lines and non-tumour human neural controls in vitro. To validate RTV efficacy in monotherapeutic and in combinatorial settings, we used patient-derived xenograft models in a series of in vivo studies. Results RTV monotherapy induced a selective antineoplastic response and demonstrated cytostatic and anti-migratory activity at clinical plasma peak levels. Additional exposure to temozolomide or irradiation further enhanced the effects synergistically, fostered by mechanisms of autophagy and increased endoplasmic reticulum stress. In xenograft models, we consequently observed increasing overall survival under the combinatorial effect of RTV and temozolomide. Conclusions Our data establish RTV as a valuable repositioning candidate for further exploration as an adjunct therapeutic in the clinical care of glioblastoma.