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.

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

“…In this context, KDM1A, an active subunit of the NuRD complex, has been reported to have an important role in repressing and activating target genes of the fusion protein EWS‐FLI1 . The functional role of KDM1A in Ewing sarcoma oncogenesis, alongside high expression in this and other sarcomas such as DSRCT, has made it a promising therapeutic target . In light of this, our aim was to assess the therapeutic potential of KDM1A inhibitors (ORY‐1001 and GSK2879552) in Ewing sarcoma models.…”

Histone Demethylases and Their Roles in Cancer Epigenetics

“…Although several KDM1A inhibitors have been synthesized, only a few show clinical utility. A highly specific, non-competitive KDM1A inhibitor, HCI-2509 (SP2509), has been effective in inducing apoptosis in Ewing sarcoma cell lines, particularly those that express the EWS-FLI1 fusion protein, alone and in combination with other anticancer agents [76]. HCI-2509 produces similar effects on other cancer cell lines, such as poorly differentiated endometrial carcinoma and AML [77,78].…”

Epigenetic and genetic changes in soft tissue sarcomas: a review

“…Additionally, epigenetic marks and miRNAs may serve as new markers to evaluate prognosis. Lysine demethylase inhibitors and HDAC inhibitors show promise in the treatment for sarcomas such as Ewing's sarcoma . In rhabdomyosarcoma, miR‐101, miR‐26a and miR‐214 induce myogenic differentiation and are downregulated by EZH2 Upregulation of these miRNAs could thus be potential means of future therapy in this disease .…”