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8 results on '"Roderwieser, A."'

2. A mechanistic classification of clinical phenotypes in neuroblastoma

Author

Ackermann, Sandra, Cartolano, Maria, Hero, Barbara, Welte, Anne, Kahlert, Yvonne, Roderwieser, Andrea, Bartenhagen, Christoph, Walter, Esther, Gecht, Judith, Kerschke, Laura, Volland, Ruth, Menon, Roopika, Heuckmann, Johannes M., Gartlgruber, Moritz, Hartlieb, Sabine, Henrich, Kai-Oliver, Okonechnikov, Konstantin, Altmüller, Janine, Nürnberg, Peter, Lefever, Steve, de Wilde, Bram, Sand, Frederik, Ikram, Fakhera, Rosswog, Carolina, Fischer, Janina, Theissen, Jessica, Hertwig, Falk, Singhi, Aatur D., Simon, Thorsten, Vogel, Wenzel, Perner, Sven, Krug, Barbara, Schmidt, Matthias, Rahmann, Sven, Achter, Viktor, Lang, Ulrich, Vokuhl, Christian, Ortmann, Monika, Büttner, Reinhard, Eggert, Angelika, Speleman, Frank, O’Sullivan, Roderick J., Thomas, Roman K., Berthold, Frank, Vandesompele, Jo, Schramm, Alexander, Westermann, Frank, Schulte, Johannes H., Peifer, Martin, and Fischer, Matthias

Published
2018

3. Telomerase-targeting compounds Imetelstat and 6-thio-dG act synergistically with chemotherapy in high-risk neuroblastoma models

Author

Janina Fischer-Mertens, Felix Otte, Andrea Roderwieser, Carolina Rosswog, Yvonne Kahlert, Lisa Werr, Anna-Maria Hellmann, Maya Berding, Bill Chiu, Christoph Bartenhagen, and Matthias Fischer

Subjects
Cancer Research, General Medicine, Xenograft Model Antitumor Assays, Mice, Neuroblastoma, Oncology, Doxorubicin, Cell Line, Tumor, Humans, Animals, Molecular Medicine, Telomerase, Etoposide, Cell Proliferation
Abstract

Background The majority of high-risk neuroblastomas harbor telomerase activity, and telomerase-interacting compounds, such as 6-thio-2’-deoxyguanosine (6-thio-dG), have been found to impair the growth of telomerase-positive neuroblastoma cell lines. It has remained unclear, however, how such drugs can be combined with other compounds used in current treatment concepts for neuroblastoma patients. Methods Growth-inhibitory effects of varying concentrations of 6-thio-dG in combination with etoposide, doxorubicin or ceritinib were determined in eight telomerase-positive neuroblastoma cell lines with distinct genetic backgrounds. Tumor growth inhibition of subcutaneous xenografts from three different cell lines was assessed upon treatment with 6-thio-dG, the competitive telomerase inhibitor imetelstat, etoposide, or combinations of these compounds. Results Robust synergistic anti-tumor effects were observed for combinations of 6-thio-dG and etoposide or doxorubicin, but not for 6-thio-dG and ceritinib, in telomerase-positive neuroblastoma cell lines in vitro. Treatment of mouse xenografts with combinations of 6-thio-dG and etoposide significantly attenuated tumor growth and improved mouse survival over etoposide alone in two of three cell line models. Treatment of xenograft tumors by imetelstat monotherapy decreased telomerase activity by roughly 50% and significantly improved survival over control in all three models, whereas treatment with imetelstat plus etoposide led to enhanced survival over etoposide monotherapy in one model. Mechanistically, the synergistic effect was found to be due to both increased apoptosis and cell cycle arrest. Conclusion Our study indicates that telomerase is an actionable target in telomerase-positive neuroblastoma, and demonstrates that combination therapies including telomerase-interacting compounds may improve the efficacy of established cytotoxic drugs. Targeting telomerase may thus represent a therapeutic option in high-risk neuroblastoma patients.

Published
2022
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4. Telomerase Is a Prognostic Marker of Poor Outcome and a Therapeuctic Target in Neuroblastoma

Author

Roderwieser, Andrea, Sand, Frederik, Walter, Esther, Fischer, Janina, Gecht, Judith, Bartenhagen, Christoph, Ackermann, Sandra, Otte, Felix, Welte, Anne, Kahlert, Yvonne, Lieberz, Daniela, Hertwig, Falk, Reinhardt, H. Christian, Simon, Thorsten, Peifer, Martin, Ortmann, Monika, Buettner, Reinhard, Hero, Barbara, O'Sullivan, Roderick J., Berthold, Frank, Fischer, Matthias, Roderwieser, Andrea, Sand, Frederik, Walter, Esther, Fischer, Janina, Gecht, Judith, Bartenhagen, Christoph, Ackermann, Sandra, Otte, Felix, Welte, Anne, Kahlert, Yvonne, Lieberz, Daniela, Hertwig, Falk, Reinhardt, H. Christian, Simon, Thorsten, Peifer, Martin, Ortmann, Monika, Buettner, Reinhard, Hero, Barbara, O'Sullivan, Roderick J., Berthold, Frank, and Fischer, Matthias

Abstract

PURPOSE Telomere maintenance is a hallmark of high-risk neuroblastoma; however, the contribution of telomerase and alternative lengthening of telomeres (ALT) to clinical phenotypes has remained unclear. We aimed to determine the clinical relevance of telomerase activation versus ALT as biomarkers in pretreatment neuroblastoma and to assess the potential value of telomerase as a therapeutic target. MATERIALS AND METHODS The genomic status of TERT and MYCN was assessed in 457 pretreatment neuroblastomas by fluorescence in situ hybridization. ALT was examined in 273 of 457 tumors by detection of ALT-associated promyelocytic leukemia nuclear bodies, and TERT expression was determined by microarrays in 223 of these. Cytotoxic effects of telomerase-interacting compounds were analyzed in neuroblastoma cell lines in vitro and in vivo. RESULTS We detected TERT rearrangements in 46 of 457 cases (10.1%), MYCN amplification in 93 of 457 cases (20.4%), and elevated TERT expression in tumors lacking TERT or MYCN alterations in 10 of 223 cases (4.5%). ALT activation was found in 49 of 273 cases (17.9%). All these alterations occurred almost mutually exclusively and were associated with unfavorable prognostic variables and adverse outcome. The presence of activated telomerase (ie, TERT rearrangements, MYCN amplification, or high TERT expression without these alterations) was associated with poorest overall survival and was an independent prognostic marker in multi-variable analyses. We also found that the telomerase-interacting compound 6-thio-2'-deoxyguanosine effectively inhibited viability and proliferation of neuroblastoma cells bearing activated telomerase. Similarly, tumor growth was strongly impaired upon 6-thio-2'-deoxyguanosine treatment in telomerase-positive neuroblastoma xenografts in mice. CONCLUSION Our data suggest telomerase activation and ALT define distinct neuroblastoma subgroups with adverse outcome and that telomerase may represent a promising therapeutic targe

Published
2019

6. Telomerase Is a Prognostic Marker of Poor Outcome and a Therapeutic Target in Neuroblastoma

Author

Roderwieser, Andrea, primary, Sand, Frederik, additional, Walter, Esther, additional, Fischer, Janina, additional, Gecht, Judith, additional, Bartenhagen, Christoph, additional, Ackermann, Sandra, additional, Otte, Felix, additional, Welte, Anne, additional, Kahlert, Yvonne, additional, Lieberz, Daniela, additional, Hertwig, Falk, additional, Reinhardt, H. Christian, additional, Simon, Thorsten, additional, Peifer, Martin, additional, Ortmann, Monika, additional, Büttner, Reinhard, additional, Hero, Barbara, additional, O’Sullivan, Roderick J., additional, Berthold, Frank, additional, and Fischer, Matthias, additional

Published
2019
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8. A Mechanistic Classification of Clinical Phenotypes in Neuroblastoma

Author

Ackermann, S., Cartolano, M., Hero, B., Roderwieser, A., Bartenhagen, C., Rosswog, C., Hertwig, F., Simon, T., Eggert, A., Speleman, F., Buettner, R., O Sullivan, R., Thomas, R., Frank Berthold, Vandesompele, J., Schramm, A., Westermann, F., Schulte, J., Peifer, M., and Fischer, M.

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