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, Marcel Kool

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1607-1617
Number of pages11
JournalNeuro-Oncology
Volume19
Issue number12
DOIs
Publication statusPublished - 1 Dec 2017
Externally publishedYes

Keywords

  • actinomycin D
  • brain tumor
  • ETMR
  • topotecan
  • volasertib

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