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

Emily R. Theisen, Kathleen I. Pishas, Ranajeet S. Saund and Stephen L. Lessnick _

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Oncotarget. 2016; 7:17616-17630. https://doi.org/10.18632/oncotarget.7124

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Emily R. Theisen1,*, Kathleen I. Pishas1,2,*, Ranajeet S. Saund1,* and Stephen L. Lessnick1,3

1 Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA

2 Cancer Therapeutics Laboratory, Centre for Personalized Cancer Medicine, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia

3 Division of Pediatric Hematology/Oncology/Bone Marrow Transplant at The Ohio State University, Columbus, Ohio, USA

* These authors have contributed equally to this work and should be considered as co-first authors

Correspondence to:

Stephen L. Lessnick, email:

Keywords: Ewing sarcoma, LSD1, EWS-FLI, epigenetics, methylation

Received: September 23, 2015 Accepted: January 23, 2016 Published: February 02, 2016


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.

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