Abstract 3679: Inhibition of LSD1 disrupts global EWS/ETS transcriptional function in Ewing sarcoma

Autor: Timothy S. Mulvihill, Emily R. Theisen, Savita Sankar, Sunil Sharma, Venkataswamy Sorna, Stephen L. Lessnick, Jared Bearss
Rok vydání: 2014
Předmět:
Zdroj: Cancer Research. 74:3679-3679
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2014-3679
Popis: Ewing sarcoma is an aggressive pediatric bone tumor characterized by an absolute reliance on the transcriptional activity of the EWS/ETS family of transcription factor fusion oncoproteins. The most common fusion is EWS/FLI, present in 85-95% of cases, though less common fusions include EWS/ERG, EWS/ETV1, EWS/ETV4 and EWS/FEV. EWS/FLI utilizes lysine-specific demethylase 1 (LSD1) as member of the NuRD complex to mediate transcriptional repression of critical tumor suppressors in Ewing sarcoma. LSD1 overexpression has been observed in clinical samples from Ewing sarcoma patients and small molecule blockade of LSD1 using tranylcypromine has been suggested as a therapeutic approach for Ewing sarcoma. We therefore evaluated the effects of LSD1 inhibition with the small molecule inhibitor, HCI-2509, in both in vitro and in vivo models of Ewing sarcoma. HCI-2509 is an LSD1 inhibitor with a Ki of ∼30 nM and multiple Ewing sarcoma cell lines show IC50s in cell viability assays from 500 nM-1 μM. Using RNA-seq, we show that HCI-2509 dramatically reverses both the up- and downregulated transcriptional profiles of both EWS/FLI and EWS/ERG accompanied by the induction of apoptosis and disruption of oncogenic phenotypes modulated by EWS/FLI. We further developed a 9-gene panel based on the RNA-seq data to assess the transcriptional phenotype of HCI-2509 in additional cell lines and showed that it HCI-2509 disrupted both EWS/FLI-activated and -repressed genes similarly across the tested Ewing sarcoma cell lines. HCI-2509 impaired transformation of Ewing sarcoma cell lines in colony forming assays with IC50s from from 25 nM-1 μM. Notably, HCI-2509 displayed single-agent efficacy in multiple xenograft models. We investigated the PK/PD relationship using tumor histone H3K4 and H3K9 methylation. Taken together, these data suggest that epigenetic modulation through LSD1 inhibition may be a therapeutic strategy for Ewing sarcoma, and highlight a critical dual role for LSD1 in the oncogenic transcriptional activity of EWS/ETS proteins. Citation Format: Emily Rose Theisen, Savita Sankar, Jared Bearss, Timothy Mulvihill, Venkataswamy Sorna, Sunil Sharma, Stephen L. Lessnick. Inhibition of LSD1 disrupts global EWS/ETS transcriptional function in Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3679. doi:10.1158/1538-7445.AM2014-3679
Databáze: OpenAIRE
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