Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting

Abstract

Ewing sarcoma is an aggressive primary pediatric bone tumor, often diagnosed in adolescents and young adults. A pathognomonic reciprocal chromosomal translocation results in a fusion gene coding for a protein which derives its N-terminus from a FUS/EWS/TAF15 (FET) protein family member, commonly EWS, and C-terminus containing the DNA-binding domain of an ETS transcription factor, commonly FLI1. Nearly 85% of cases express the EWS-FLI protein which functions as a transcription factor and drives oncogenesis. As the primary genomic lesion and a protein which is not expressed in normal cells, disrupting EWS-FLI function is an attractive therapeutic strategy for Ewing sarcoma. However, transcription factors are notoriously difficult targets for the development of small molecules. Improved understanding of the oncogenic mechanisms employed by EWS-FLI to hijack normal cellular programming has uncovered potential novel approaches to pharmacologically block EWS-FLI function. In this review we examine targeting the chromatin regulatory enzymes recruited to conspire in oncogenesis with a focus on the histone lysine specific demethylase 1 (LSD1). LSD1 inhibitors are being aggressively investigated in acute myeloid leukemia and the results of early clinical trials will help inform the future use of LSD1 inhibitors in sarcoma. High LSD1 expression is observed in Ewing sarcoma patient samples and mechanistic and preclinical data suggest LSD1 inhibition globally disrupts the function of EWS-ETS proteins.

Keywords: EWS-FLI; Ewing sarcoma; LSD1; epigenetics; methylation.

Figure 1. Chemical structure of HCI-2509 and GSK-2879552, reversible and irreversible inhibitors of LSD1 respectively

Figure 2. EWS-FLI interacts with multiple partners to cause gene specific activation and repression on the road to oncogenesis

LSD1 inhibition (LSDi) negatively impacts direct transcriptional targets of EWS-FLI, in a manner distinct from HDAC inhibition (HDACi). Moreover, there is data to suggest additional roles for both LSD1 and HDACs in the downstream effects leading to oncogenesis, and these remain an area of active study.