One oncogene, several vulnerabilities: EWS/FLI targeted therapies for Ewing sarcoma

Abstract

EWS/FLI is the defining mutation of Ewing sarcoma. This oncogene drives malignant transformation and progression and occurs in a genetic background characterized by few other recurrent cooperating mutations. In addition, the tumor is absolutely dependent on the continued expression of EWS/FLI to maintain the malignant phenotype. However, EWS/FLI is a transcription factor and therefore a challenging drug target. The difficulty of directly targeting EWS/FLI stems from unique features of this fusion protein as well as the network of interacting proteins required to execute the transcriptional program. This network includes interacting proteins as well as upstream and downstream effectors that together reprogram the epigenome and transcriptome. While the vast number of proteins involved in this process challenge the development of a highly specific inhibitors, they also yield numerous therapeutic opportunities. In this report, we will review how this vast EWS-FLI transcriptional network has been exploited over the last two decades to identify compounds that directly target EWS/FLI and/or associated vulnerabilities.

Keywords: EWS/FLI; Ewing sarcoma; Molecular pharmacology; Transcription factor targeting.

Fig. 1

Therapeutic approaches targeting EWS/FLI expression. Ewing cells do not tolerate either an increase or decrease in EWS/FLI expression. Approaches modulating molecular chaperones or activating E3 ubiquitin ligases may deplete EWS/FLI expression leading to degradation either in the lysosome or proteosome. Inhibition of EWS/FLI associated de-ubiquitinases also could be effective because the cell does not tolerate increased EWS/FLI.

Fig. 2

EWS/FLI associated epigenetic targets. EWS/FLI requires alterations in chromatin structure to generate its oncogenic transcriptome. Therefore, a variety of compounds and targets have been evaluated to modulated the associated epigenome with great promise.

Fig. 3

Targeting the DNA damage response. EWS/FLI is known to bind and regulate the expression/activity of multiple proteins involved in the DNA damage response. These pathways have been explored as therapeutic targets both alone, sequentially and in combination with EWS/FLI targeted agents.

Fig. 4

Blocking EWS/FLI driven transcription. Transcription is a multi-step process. Compounds have been identified that interfere with the DNA binding of EWS/FLI, promoter escape or productive elongation with varying degrees of specificity. Sequential targeting of this process has been proposed to increase activity and perhaps specificity.