Experimental Local Therapy in High-Risk Neuroblastoma
Hematology, Oncology
Final Report Abstract
The majority of high-risk neuroblastomas harbor telomerase activity, and telomeraseinteracting 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 used as local therapy or be combined with other compounds used in current treatment concepts for neuroblastoma patients. Growth-inhibitory effects of varying concentrations of 6-thio-dG in combination with etoposide were determined in eight telomerase-positive neuroblastoma cell lines with distinct genetic backgrounds. Tumor growth inhibition of subcutaneous or orthotopic 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. Robust synergistic anti-tumor effects were observed for combinations of 6-thio-dG and etoposide 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. In orthotopic xenografts, local application of high-dosage 6-thio-dG with/without etoposide is comparable to a systemic therapy. 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.
Publications
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Telomerase-targeting compounds Imetelstat and 6-thio-dG act synergistically with chemotherapy in high-risk neuroblastoma models. Cellular Oncology, 45(5), 991-1003.
Fischer-Mertens, Janina; Otte, Felix; Roderwieser, Andrea; Rosswog, Carolina; Kahlert, Yvonne; Werr, Lisa; Hellmann, Anna-Maria; Berding, Maya; Chiu, Bill; Bartenhagen, Christoph & Fischer, Matthias
