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Start Over Author "Boeva V" Publisher american association for cancer research (aacr)
3 results on '"Boeva V"'

1. Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy

Author

Chen, J, Nelson, C, Wong, M, Tee, AE, Liu, PY, La, T, Fletcher, JI, Kamili, A, Mayoh, C, Bartenhagen, C, Trahair, TN, Xu, N, Jayatilleke, N, Peng, H, Atmadibrata, B, Cheung, BB, Lan, Q, Bryan, TM, Mestdagh, P, Vandesompele, J, Combaret, V, Boeva, V, Wang, JY, Janoueix-Lerosey, I, Cowley, MJ, MacKenzie, KL, Dolnikov, A, Li, J, Polly, P, Marshall, GM, Reddel, RR, Norris, MD, Haber, M, Fischer, M, Zhang, XD, Pickett, HA, and Liu, T

Subjects
1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeTERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma.Experimental designAnticancer 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.ResultsThe 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.ConclusionsOTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.

Published
2020

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

Author

Chen, J ; https://orcid.org/0000-0002-6774-0199, Nelson, C, Wong, M ; https://orcid.org/0000-0002-0324-8664, Tee, AE, Liu, PY ; https://orcid.org/0000-0001-9237-5990, La, T, Fletcher, JI ; https://orcid.org/0000-0003-2949-9469, Kamili, A ; https://orcid.org/0000-0002-4864-1195, Mayoh, C ; https://orcid.org/0000-0002-6398-3046, Bartenhagen, C, Trahair, TN ; https://orcid.org/0000-0002-3295-228X, Xu, N, Jayatilleke, N ; https://orcid.org/0000-0003-4086-0622, Wong, M, Peng, H, Atmadibrata, B, Cheung, BB ; https://orcid.org/0000-0001-8784-860X, Lan, Q, Bryan, TM, Mestdagh, P, Vandesompele, J, Combaret, V, Boeva, V, Wang, JY ; https://orcid.org/0000-0002-1325-7943, Janoueix-Lerosey, I, Cowley, MJ ; https://orcid.org/0000-0002-9519-5714, MacKenzie, KL, Dolnikov, A, Li, J, Polly, P ; https://orcid.org/0000-0001-7250-5217, Marshall, GM, Reddel, RR, Norris, MD ; https://orcid.org/0000-0002-0632-4589, Haber, M ; https://orcid.org/0000-0003-2036-8817, Fischer, M, Zhang, XD, Pickett, HA, Liu, T ; https://orcid.org/0000-0001-6244-7316, Chen, J ; https://orcid.org/0000-0002-6774-0199, Nelson, C, Wong, M ; https://orcid.org/0000-0002-0324-8664, Tee, AE, Liu, PY ; https://orcid.org/0000-0001-9237-5990, La, T, Fletcher, JI ; https://orcid.org/0000-0003-2949-9469, Kamili, A ; https://orcid.org/0000-0002-4864-1195, Mayoh, C ; https://orcid.org/0000-0002-6398-3046, Bartenhagen, C, Trahair, TN ; https://orcid.org/0000-0002-3295-228X, Xu, N, Jayatilleke, N ; https://orcid.org/0000-0003-4086-0622, Wong, M, Peng, H, Atmadibrata, B, Cheung, BB ; https://orcid.org/0000-0001-8784-860X, Lan, Q, Bryan, TM, Mestdagh, P, Vandesompele, J, Combaret, V, Boeva, V, Wang, JY ; https://orcid.org/0000-0002-1325-7943, Janoueix-Lerosey, I, Cowley, MJ ; https://orcid.org/0000-0002-9519-5714, MacKenzie, KL, Dolnikov, A, Li, J, Polly, P ; https://orcid.org/0000-0001-7250-5217, Marshall, GM, Reddel, RR, Norris, MD ; https://orcid.org/0000-0002-0632-4589, Haber, M ; https://orcid.org/0000-0003-2036-8817, Fischer, M, Zhang, XD, Pickett, HA, and Liu, T ; https://orcid.org/0000-0001-6244-7316

Abstract

Purpose: TERT gene rearrangement with transcriptional superenhancers 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.

Published
2021

3. Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.

Author

Chen, J, Nelson, C, Wong, M, Tee, AE, Liu, PY, La, T, Fletcher, JI, Kamili, A, Mayoh, C, Bartenhagen, C, Trahair, TN, Xu, N, Jayatilleke, N, Peng, H, Atmadibrata, B, Cheung, BB, Lan, Q, Bryan, TM, Mestdagh, P, Vandesompele, J, Combaret, V, Boeva, V, Wang, JY, Janoueix-Lerosey, I, Cowley, MJ, MacKenzie, KL, Dolnikov, A, Li, J, Polly, P, Marshall, GM, Reddel, RR, Norris, MD, Haber, M, Fischer, M, Zhang, XD, Pickett, HA, Liu, T, Chen, J, Nelson, C, Wong, M, Tee, AE, Liu, PY, La, T, Fletcher, JI, Kamili, A, Mayoh, C, Bartenhagen, C, Trahair, TN, Xu, N, Jayatilleke, N, Peng, H, Atmadibrata, B, Cheung, BB, Lan, Q, Bryan, TM, Mestdagh, P, Vandesompele, J, Combaret, V, Boeva, V, Wang, JY, Janoueix-Lerosey, I, Cowley, MJ, MacKenzie, KL, Dolnikov, A, Li, J, Polly, P, Marshall, GM, Reddel, RR, Norris, MD, Haber, M, Fischer, M, Zhang, XD, Pickett, HA, and Liu, T

Abstract

Purpose

TERT gene rearrangement with transcriptional superenhancers 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
Published
2021

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