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Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination
Jingwei Chen1,2, Christopher Nelson3, Matthew Wong1,2
1Children's Cancer Institute, Randwick, Sydney, Australia.
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.
Insights
A new combination therapy using OTX015 and carfilzomib shows promise for treating TERT-rearranged neuroblastoma. This targeted approach effectively reduces TERT expression and induces cancer cell death, offering hope for a new clinical trial.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- TERT gene rearrangement drives neuroblastoma via TERT overexpression.
- Currently, no targeted therapies exist for TERT-rearranged neuroblastoma.
Purpose of the Study:
- To identify synergistic anticancer agents for TERT-rearranged neuroblastoma.
- To evaluate the efficacy of combining BET bromodomain inhibitors with other agents.
Main Methods:
- Screened an FDA-approved oncology drug library for synergy with BET inhibitors.
- Investigated OTX015 (BET inhibitor) and carfilzomib (proteasome inhibitor) combination in vitro and in vivo.
- Utilized immunoblot, flow cytometry, and xenograft mouse models.
Main Results:
- Carfilzomib demonstrated the best synergy with BET inhibitors like OTX015.
- The combination therapy synergistically reduced TERT expression, induced ER stress, and promoted apoptosis in neuroblastoma cells.
- In vivo studies showed suppressed tumor progression and improved survival in mice.
Conclusions:
- OTX015 and carfilzomib combination therapy is a promising targeted treatment strategy.
- This combination is poised for translation into the first clinical trial for TERT-rearranged neuroblastoma.
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