1575381540     

505381540                        

---

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

Schmidt, Christin [Verfasserin/Verfasser]

Selt, Florian, 1984- [Verfasserin/Verfasser] ; Herold-Mende, Christel [Verfasserin/Verfasser] ; Witt, Olaf, 1965- [Verfasserin/Verfasser] ; Milde, Till [Verfasserin/Verfasser] ; Pfister, Stefan, 1974- [Verfasserin/Verfasser] ; Korshunov, Andrey [Verfasserin/Verfasser] ; Kool, Marcel [Verfasserin/Verfasser]

Neuro-Oncology : official journal of the World Federation of Neuro-Oncology . - Oxford : Oxford Univ. Press ; Durham, NC : Duke University Medical Center, 1999-. - Bd. 19 (2017), 12, S. 1607-1617 = 11 S.

Englisch

Gesehen am 22.05.2018

Digital Object Identifier (DOI): 10.1093/neuonc/nox093

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.