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Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy

(2021) CLINICAL CANCER RESEARCH. 27(5). p.1438-1451
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Abstract
Purpose: TERT gene rearrangement with transcriptional super-enhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.
Keywords
SELECTIVE-INHIBITION, MULTIPLE-MYELOMA, DOSE-ESCALATION, ACUTE-LEUKEMIA, OPEN-LABEL, PHASE-II, TELOMERASE, BORTEZOMIB, OTX015, MYC

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MLA
Chen, Jingwei, et al. “Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.” CLINICAL CANCER RESEARCH, vol. 27, no. 5, 2021, pp. 1438–51, doi:10.1158/1078-0432.CCR-20-3044.
APA
Chen, J., Nelson, C., Wong, M., Tee, A. E., Liu, P. Y., La, T., … Liu, T. (2021). Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy. CLINICAL CANCER RESEARCH, 27(5), 1438–1451. https://doi.org/10.1158/1078-0432.CCR-20-3044
Chicago author-date
Chen, Jingwei, Christopher Nelson, Matthew Wong, Andrew E. Tee, Pei Y. Liu, Ting La, Jamie I. Fletcher, et al. 2021. “Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.” CLINICAL CANCER RESEARCH 27 (5): 1438–51. https://doi.org/10.1158/1078-0432.CCR-20-3044.
Chicago author-date (all authors)
Chen, Jingwei, Christopher Nelson, Matthew Wong, Andrew E. Tee, Pei Y. Liu, Ting La, Jamie I. Fletcher, Alvin Kamili, Chelsea Mayoh, Christoph Bartenhagen, Toby N. Trahair, Ning Xu, Nisitha Jayatilleke, Marie Wong, Hui Peng, Bernard Atmadibrata, Belamy B. Cheung, Qing Lan, Tracy M. Bryan, Pieter Mestdagh, Jo Vandesompele, Valerie Combaret, Valentina Boeva, Jenny Y. Wang, Isabelle Janoueix-Lerosey, Mark J. Cowley, Karen L. MacKenzie, Alla Dolnikov, Jinyan Li, Patsie Polly, Glenn M. Marshall, Roger R. Reddel, Murray D. Norris, Michelle Haber, Matthias Fischer, Xu D. Zhang, Hilda A. Pickett, and Tao Liu. 2021. “Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.” CLINICAL CANCER RESEARCH 27 (5): 1438–1451. doi:10.1158/1078-0432.CCR-20-3044.
Vancouver
1.
Chen J, Nelson C, Wong M, Tee AE, Liu PY, La T, et al. Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy. CLINICAL CANCER RESEARCH. 2021;27(5):1438–51.
IEEE
[1]
J. Chen et al., “Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy,” CLINICAL CANCER RESEARCH, vol. 27, no. 5, pp. 1438–1451, 2021.
@article{8705750,
  abstract     = {{Purpose: TERT gene rearrangement with transcriptional super-enhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.}},
  author       = {{Chen, Jingwei and Nelson, Christopher and Wong, Matthew and Tee, Andrew E. and Liu, Pei Y. and La, Ting and Fletcher, Jamie I. and Kamili, Alvin and Mayoh, Chelsea and Bartenhagen, Christoph and Trahair, Toby N. and Xu, Ning and Jayatilleke, Nisitha and Wong, Marie and Peng, Hui and Atmadibrata, Bernard and Cheung, Belamy B. and Lan, Qing and Bryan, Tracy M. and Mestdagh, Pieter and Vandesompele, Jo and Combaret, Valerie and Boeva, Valentina and Wang, Jenny Y. and Janoueix-Lerosey, Isabelle and Cowley, Mark J. and MacKenzie, Karen L. and Dolnikov, Alla and Li, Jinyan and Polly, Patsie and Marshall, Glenn M. and Reddel, Roger R. and Norris, Murray D. and Haber, Michelle and Fischer, Matthias and Zhang, Xu D. and Pickett, Hilda A. and Liu, Tao}},
  issn         = {{1078-0432}},
  journal      = {{CLINICAL CANCER RESEARCH}},
  keywords     = {{SELECTIVE-INHIBITION,MULTIPLE-MYELOMA,DOSE-ESCALATION,ACUTE-LEUKEMIA,OPEN-LABEL,PHASE-II,TELOMERASE,BORTEZOMIB,OTX015,MYC}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{1438--1451}},
  title        = {{Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-20-3044}},
  volume       = {{27}},
  year         = {{2021}},
}

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