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

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

doi:10.18632/oncotarget.7124

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.

Highlights

First described by James Ewing in 1921 as “diffuse endothelioma of bone,” Ewing sarcoma is the third most common malignant bone neoplasia diagnosed in children and adolescents [1, 2]
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

Summary

INTRODUCTION

First described by James Ewing in 1921 as “diffuse endothelioma of bone,” Ewing sarcoma is the third most common malignant bone neoplasia diagnosed in children and adolescents [1, 2]. Another study showed that an E3 ubiquitin ligase, Jade-2 (jade family PHD finger 2) can negatively regulate LSD1 in developing mouse cortical neurons and zebrafish embryos [102] It remains to be explored whether these regulatory mechanisms are active in different cancers, including Ewing sarcoma. Overexpression of LSD1 (mRNA and/ or protein) is reported across numerous malignancies, few studies have evaluated whether LSD1 expression correlates with either cancer progression or overall survival For those studies that have investigated the role of LSD1, limited patient cohort size and lack of clinical follow-up data has generally impeded the ability of studies to achieve statistical significance. Dose Escalation Study of Tranylcypromine (TCP) in Combination With ATRA (Tretinoin) for Adult Patients With Acute Myelogenous Leukemia and

NCT02273102

Findings

CONCLUSIONS