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Telomerase-targeting compounds Imetelstat and 6-thio-dG act synergistically with chemotherapy in high-risk
Janina Fischer-Mertens1, Felix Otte1,2, Andrea Roderwieser1,2,3
1Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Background:
The majority of high-risk neuroblastomas harbor telomerase activity, and telomerase-interacting 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 be combined with other compounds used in current treatment concepts for neuroblastoma patients.
Methods:
Growth-inhibitory effects of varying concentrations of 6-thio-dG in combination with etoposide, doxorubicin or ceritinib were determined in eight telomerase-positive neuroblastoma cell lines with distinct genetic backgrounds. Tumor growth inhibition of subcutaneous 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.
Results:
Robust synergistic anti-tumor effects were observed for combinations of 6-thio-dG and etoposide or doxorubicin, but not for 6-thio-dG and ceritinib, 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.
Conclusion:
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.
Insights
Combining telomerase inhibitors like 6-thio-2'-deoxyguanosine (6-thio-dG) with etoposide or doxorubicin shows synergistic effects against neuroblastoma. This combination therapy targeting telomerase may improve outcomes for high-risk neuroblastoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- High-risk neuroblastomas frequently exhibit telomerase activity.
- Telomerase-interacting compounds, such as 6-thio-2'-deoxyguanosine (6-thio-dG), inhibit telomerase-positive neuroblastoma cell growth.
- The combination potential of 6-thio-dG with existing neuroblastoma treatments was previously unclear.
Purpose of the Study:
- To investigate the efficacy of combining 6-thio-dG with etoposide, doxorubicin, or ceritinib against neuroblastoma.
- To evaluate the impact of telomerase-targeting agents and combination therapies on neuroblastoma xenografts.
- To elucidate the mechanisms underlying synergistic anti-tumor effects.
Main Methods:
- Assessed growth inhibition of eight neuroblastoma cell lines treated with 6-thio-dG and other agents.
- Evaluated tumor growth and survival in mouse xenograft models using 6-thio-dG, imetelstat, and etoposide, alone and in combination.
- Analyzed telomerase activity and tumor cell apoptosis and cell cycle progression.
Main Results:
- Combinations of 6-thio-dG with etoposide or doxorubicin demonstrated robust synergistic anti-tumor effects in vitro.
- In vivo, 6-thio-dG and etoposide combination therapy significantly reduced tumor growth and improved survival in two of three xenograft models.
- Imetelstat monotherapy reduced telomerase activity and improved survival; combination with etoposide showed enhanced survival in one model. Synergistic effects were linked to increased apoptosis and cell cycle arrest.
Conclusions:
- Telomerase is a viable therapeutic target in telomerase-positive neuroblastoma.
- Combination therapies involving telomerase-interacting compounds can enhance the effectiveness of established cytotoxic drugs.
- Targeting telomerase presents a promising therapeutic strategy for high-risk neuroblastoma.
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