Abstract 2035: Anti-epileptic drug targets Ewing sarcoma.
Authors: Kayarthodi Shubhalaxmi , Fujimura Yasuo , Rungsrisuriyachai Kunchala , Fang Jinbo , Rao Veena , Reddy Shyam P. 
Published: August 2014

Abstract
Ewing sarcoma is a highly aggressive and metastatic bone or soft tissue tumor that affects children and adolescents. It is characterized by chromosomal translocations involving EWS gene and one of the ETS (Erythroblastosis virus E26 transformation-specific) families of transcription factors (ERG, FLI1, ETV1, ETV4, E1AF and FEV). All of the fusion genes juxtapose the EWS gene to an ETS related gene. Previously our laboratory has discovered several ETS oncogenes that have shown to play major roles in human cancers. ERG (ETS Related Gene), an important member of the ETS family genes, discovered by Drs. Reddy and Rao is shown to be involved in Ewing sarcoma. Our laboratory has previously demonstrated that ERG protein functions as a sequence specific transcriptional activator. Our preliminary results have shown that ERG and aberrant EWS-ERG proteins inhibit RXR transcriptional activation and apoptosis. These results suggest that transcriptional inhibition may play a major role in apoptosis function. Using a cell based assay system developed in our laboratory that measures the inhibitory activities of ERG proteins, we screened for known drugs that can reverse the inhibitory effects of RXR transcriptional activity. Since HDACs regulate nuclear receptors, we hypothesized that anti-epileptic drug, valproic acid and trichostatin-A (HDAC inhibitors) may reverse the inhibitory properties of EWS-ERG oncoprotein on RXR transcriptional activity and they can be used as therapeutic agents in Ewing sarcoma. Methods: Cell based assays were used to measure the RXR transcriptional activation function and in vivo assays were used to study the cell viability and apoptosis activity. Results: (1) Anti-epileptic drugs, valproic acid (VPA) and trichostatin-A (TSA) have shown to reverse the inhibitory effect of EWS-ERG on RXR transcriptional activity. (2) VPA and TSA inhibit the cell growth of Ewing sarcoma cells expressing EWS-ERG onco-protein. (3) VPA induce apoptosis in Ewing sarcoma cells. (4) VPA induce the expression of RXR target genes. Conclusion: Ewing sarcoma requires highly intensive chemotherapy along with surgery and/or radiation. Current therapies are associated with significant short and long term side effects. Hence new therapeutic approaches are needed. The above results suggest that the anti-epileptic drug VPA could be used as a potential treatment option for regulation of the function of EWS-ERG onco-protein. Thus, a promising drug with a new potential will have profound impact on prevention, management and treatment of Ewing family of cancers.
Citation Format: Shubhalaxmi Kayarthodi, Yasuo Fujimura, Kunchala Rungsrisuriyachai, Jinbo Fang, Veena Rao, Shyam P. Reddy. Anti-epileptic drug targets Ewing sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2035. doi:10.1158/1538-7445.AM2013-2035