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Targeted activity of histone deacetylase inhibition in synovial sarcoma

University of British Columbia

Synovial sarcoma is an aggressive soft tissue cancer affecting primarily adolescents and young adults and characterized by the known chimeric fusion oncoprotein SS18-SSX resulting from a t(X;18) translocation. Oncoprotein-mediated interactions with chromatin-modification proteins are known to influence transformation; however targeted therapies are not currently available. Patients remain at high-risk for local recurrence and metastasis and see a 10-year survival rate of approximately 50%. Accordingly, it was hypothesized that therapeutic compounds able to disrupt the SS18-SSX driving complex would be clinically effective against synovial sarcoma. The proximity ligation assay was employed to study the drug-mediated disruption of the key SS18-SSX-mediated protein interactions that drive sarcomagenesis, and was developed for use to demonstrate targeted drug efficacy. Results identified HDAC inhibitors as potent in disrupting the oncogenic protein complex. The combination of HDAC and proteasome inhibitors was further found to be synergistic against synovial sarcoma. This pre-clinical study was used as support for a novel clinical trial proposal for translocation-associated soft tissue sarcomas. The effects of HDAC inhibition on genome-wide transcription patterns was further assessed by RNA-seq analysis. Uniquely to synovial sarcoma, it was revealed that HDAC inhibition elicits loss of the SS18-SSX oncoprotein and provokes significant pro-apoptotic BIK expression correlating to CDKN2A reactivation. From this, the contributing role of CDKN2A reactivation and reactive oxygen species accumulation in HDAC-inhibitor mediated apoptosis in synovial sarcoma was demonstrated.

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2017-08-14

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62602

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/