Preclinical drug screen reveals topotecan, actinomycin D, and volasertib as potential new therapeutic candidates for ETMR brain tumor patients

• Verfasst von: Schmidt, Christin [VerfasserIn]
• Verfasst von: Selt, Florian [VerfasserIn]
• Verfasst von: Herold-Mende, Christel [VerfasserIn]
• Verfasst von: Witt, Olaf [VerfasserIn]
• Verfasst von: Milde, Till [VerfasserIn]
• Verfasst von: Pfister, Stefan [VerfasserIn]
• Verfasst von: Korshunov, Andrey [VerfasserIn]
• Verfasst von: Kool, Marcel [VerfasserIn]
• Titel: Preclinical drug screen reveals topotecan, actinomycin D, and volasertib as potential new therapeutic candidates for ETMR brain tumor patients
• Verf.angabe: Christin Schmidt, Nil A. Schubert, Sebastian Brabetz, Norman Mack, Benjamin Schwalm, Jennifer A. Chan, Florian Selt, Christel Herold-Mende, Olaf Witt, Till Milde, Stefan M. Pfister, Andrey Korshunov, and Marcel Kool
• E-Jahr: 2017
• Jahr: 08 May 2017
• Umfang: 11 S.
• Fussnoten: Gesehen am 22.05.2018
• Titel Quelle: Enthalten in: Neuro-Oncology
• Ort Quelle: Oxford : Oxford Univ. Press, 1999
• Jahr Quelle: 2017
• Band/Heft Quelle: 19(2017), 12, Seite 1607-1617
• ISSN Quelle: 1523-5866
• DOI: doi:10.1093/neuonc/nox093
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1575381540

Abstract

Background: Embryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the World Health Organization classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a preclinical drug screen in order to inform potentially more active clinical trial protocols. Methods: We have carried out an in vitro and in vivo drug screen using the ETMR cell line BT183 and its xenograft model. Furthermore, we have generated the first patient-derived xenograft (PDX) model for ETMR and evaluated our top drug candidates in an in vitro drug screen using this model. Results: BT183 cells are very sensitive to the topoisomerase inhibitors topotecan and doxorubicin, to the epigenetic agents decitabine and panobinostat, to actinomycin D, and to targeted drugs such as the polo-like kinase 1 (PLK1) inhibitor volasertib, the aurora kinase A inhibitor alisertib, and the mammalian target of rapamycin (mTOR) inhibitor MLN0128. In xenograft mice, monotherapy with topotecan, volasertib, and actinomycin D led to a temporary response in tumor growth and a significant increase in survival. Finally, using multi-agent treatment regimens of topotecan or doxorubicin combined with methotrexate and vincristine, the response in tumor growth and survival was further increased compared with mice receiving single treatments. Conclusions: We have identified several promising candidates for combination therapies in future clinical trials for ETMR patients.