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Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA
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- Carter K. Fairchild
- VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Perkinson Building Room 4134, 1101 East Leigh St, P.O. Box 980566, Richmond, VA 23298, USA
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- Konstantinos V. Floros
- VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Perkinson Building Room 4134, 1101 East Leigh St, P.O. Box 980566, Richmond, VA 23298, USA
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- Sheeba Jacob
- VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Perkinson Building Room 4134, 1101 East Leigh St, P.O. Box 980566, Richmond, VA 23298, USA
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- Colin M. Coon
- VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Perkinson Building Room 4134, 1101 East Leigh St, P.O. Box 980566, Richmond, VA 23298, USA
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- Madhavi Puchalapalli
- Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA
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- Bin Hu
- Cancer Mouse Models Core, Virginia Commonwealth University, Richmond, VA 23298, USA
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- Hisashi Harada
- VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Perkinson Building Room 4134, 1101 East Leigh St, P.O. Box 980566, Richmond, VA 23298, USA
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- Mikhail G. Dozmorov
- Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA
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- Jennifer E. Koblinski
- Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA
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- Steven C. Smith
- Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA
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- Gregory Domson
- Department of Orthopedic Surgery, Virginia Commonwealth University, Richmond, VA 23298, USA
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- Joel D. Leverson
- AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA
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- Andrew J. Souers
- AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA
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- Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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- Hiromichi Ebi
- Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
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- Anthony C. Faber
- VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Perkinson Building Room 4134, 1101 East Leigh St, P.O. Box 980566, Richmond, VA 23298, USA
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- Sosipatros A. Boikos
- Sarcoma Program, School of Medicine and Massey Cancer Center, Virginia Commonwealth University, Goodwin Research Building, Rm 382, 401 College St. P.O. Box 980037, Richmond, VA 23298, USA
Bibliographic Information
- Published
- 2021-05-12
- Resource Type
- journal article
- Rights Information
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- https://creativecommons.org/licenses/by/4.0/
- DOI
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- 10.3390/cancers13102310
- Publisher
- MDPI AG
Description
<jats:p>Synovial sarcoma (SS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathognomonic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, an FDA-approved BCL-2 inhibitor that is revolutionizing care in some BCL-2-expressing hematological cancers, affords an intriguing therapeutic possibility to treat SS. In addition, there are now dozens of venetoclax-based combination therapies in clinical trials in hematological cancers, attributing to the limited toxicity of venetoclax. However, preclinical studies of venetoclax in SS have demonstrated an unexpected ineffectiveness. In this study, we analyzed the response of SS to venetoclax and the underlying BCL-2 family biology in an effort to understand venetoclax treatment failure and find a therapeutic strategy to sensitize SS to venetoclax. We found remarkably depressed levels of the endogenous MCL-1 inhibitor, NOXA, in SS compared to other sarcomas. Expressing NOXA led to sensitization to venetoclax, as did the addition of the MCL-1 BH3 mimetic, S63845. Importantly, the venetoclax/S63845 combination induced tumor regressions in SS patient-derived xenograft (PDX) models. As a very close analog of S63845 (S64315) is now in clinical trials with venetoclax in AML (NCT03672695), the combination of MCL-1 BH3 mimetics and venetoclax should be considered for SS patients as a new therapy.</jats:p>
Journal
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- Cancers
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Cancers 13 (10), 2310-, 2021-05-12
MDPI AG
