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, 8 (3), 5523-5539

Potential Approaches to the Treatment of Ewing's Sarcoma


Potential Approaches to the Treatment of Ewing's Sarcoma

Hongjiu Yu et al. Oncotarget.


Ewing's sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene. ES is managed with standard treatments, including chemotherapy, surgery and radiation. Although the 5-year survival rate for primary ES has improved, the survival rate for ES patients with metastases or recurrence remains low. Several novel molecular targets in ES have recently been identified and investigated in preclinical and clinical settings, and targeting the function of receptor tyrosine kinases (RTKs), the fusion protein EWS-FLI1 and mTOR has shown promise. There has also been increasing interest in the immune responses of ES patients. Immunotherapies using T cells, NK cells, cancer vaccines and monoclonal antibodies have been considered for ES, especially for recurrent patients. Because understanding the pathogenesis of ES is extremely important for the development of novel treatments, this review focuses on the mechanisms and functions of targeted therapies and immunotherapies in ES. It is anticipated that integrating the knowledge obtained from basic research and translational and clinical studies will lead to the development of novel therapeutic strategies for the treatment of ES.

Keywords: Ewing’s sarcoma; immunotherapy; targeted therapy.

Conflict of interest statement


There is no conflict of interests to disclose.


Figure 1
Figure 1. Mechanism of targeting IGF1R in ES
EWS-FLI1 binds the promoters of target genes, which increases IGF1 expression, and decreases IGFBP3 expression. IGF1 interacts with IGF1R, and activates the IGF1 pathway, which mediates cellular proliferation, survival, etc. Treatment with IGF1R inhibitors and antibodies suppresses activation of the IGF1 pathway. IGF1, insulin-like growth factor 1; IGFBP3, insulin-like growth factor binding protein 3.
Figure 2
Figure 2. Strategies to target EWS-FLI1
Suppression of the EWS-FLI1 signaling can be achieved by decreasing EWS-FLI1 expression directly using antisense oligodeoxynucleotid, siRNA, or pbi-shRNA lipoplex; repressing the transcriptional activity of EWS-FLI1 by targeting the transcriptional modulators to which EWS-FLI1 binds or the transcriptional activity of EWS-FLI1 itself; or targeting the downstream genes of EWS-FLI1.RHA, RNA helicase A; PARP1, Poly(ADP-ribose) polymerase 1; HDACs, histone deacetylases; LSD1, lysine-specific demethylase 1; AURKA, Aurora kinase A; CCK, Cholecystokinin; MSA, Methylseleninic acid; ATO, Arsenic trioxide.
Figure 3
Figure 3. Mechanism of targeting the interaction of EWS-FLI1 and RHA
a. RHA enhances the transcriptional activity of EWS-FLI1-regulated promoters. The interaction of EWS-FLI1 with RHA affects pre-mRNA processing. b. RHA helicase activity is inhibited by EWS-FLI1. Disrupting RHA binding to EWS-FLI1 by YK-4-279 reduces EWS-FLI1 activity, and restores RHA helicase activity. RHA, RNA helicase A.
Figure 4
Figure 4. Mechanism of targeting the interaction of EWS-FLI1 and PARP
EWS-FLI1 interacts with PARP1, driving PARP1 expression. PARP1 promotes the transcriptional activation by EWS-FLI1. Treatment of ES with the PARP1 inhibitor olaparib could both disrupt the interaction between EWS-FLI1 and PARP1, and impair DNA repair, which represses tumorigenesis. PARP1, Poly(ADP-ribose) polymerase 1.
Figure 5
Figure 5. Strategies of T cell priming by ES associated antigens
T cells, which are primed by the peptides of the tumor associated antigens in vitro, could recognize and kill ES cells when transferred into patients. LIPI, phospholipase A1 beta; XAGE1, X antigen family member 1; NY-ESO-1, New York esophageal squamous cell carcinoma 1.

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