Christin Schmidt1, Nil A Schubert1, Sebastian Brabetz1, Norman Mack1, Benjamin Schwalm1, Jennifer A Chan1, Florian Selt1, Christel Herold-Mende1, Olaf Witt1, Till Milde1, Stefan M Pfister1, Andrey Korshunov1, Marcel Kool1. 1. Division of Pediatric Neurooncology, German Cancer Research Center, Heidelberg, Germany; Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute and Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, Section of Pediatric Brain Tumors, University Hospital Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases, Clinical Trial Center, Heidelberg, Germany; Division of Neurosurgical Research, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany; Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
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.
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.
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