Ewing sarcoma

Abstract

Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70-80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1-FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)-Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1-FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1-FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment-related toxicity, overall survival and quality of life.

ETS transcription factors as emerging drug targets in cancer

“…It has been demonstrated that many ETS factors known to be implicated in PCa are also involved into EWS. In 85% of EWS cases, the main genetic driver event is the fusion of EWSR1 gene from chromosome 22 with FLI1 (friend leukemia virus‐induced erythroleukemia‐1) gene from chromosome 11 . The current treatment options for Ewing sarcoma include surgery, radiation, and chemotherapy.…”

“…In contrast to PCa where the N‐terminal gene fusion partner such as TMPRSS2 provides only its untranslated promoter region, EWSR1‐FLI1 (or EWS‐FLI1) represents a true fusion protein where the N‐terminal activation domain of EWSR1 is joined with the C‐terminal DNA‐binding ETS domain of FLI1 . The aberrant expression of FLI1 resulting from the fusion event causes initiation and progression of Ewing sarcoma through sustained cell proliferation, angiogenesis, genomic instability, inhibition of apoptosis and differentiation, and epigenetic reprogramming . In addition to FLI1, EWSR1 has been shown to fuse with other ETS factors including ERG (10%), FEV (1%), ETV1 (1), and ETV4 (1%) in Ewing sarcoma .…”

“…In 85% of EWS cases, the main genetic driver event is the fusion of EWSR1 gene from chromosome 22 with FLI1 (friend leukemia virus-induced erythroleukemia-1) gene from chromosome 11. 24 The current treatment options for…”

Hippo pathway effectors YAP1/TAZ induce an EWS–FLI1‐opposing gene signature and associate with disease progression in Ewing sarcoma

“…Owing to multimodal treatment concepts, 2/3 of patients with localized disease achieve sustained remission but approximately 30% relapse. Patients at relapse or with advanced disease have limited chance to survive, with a 3‐year event‐free survival of less than 25% . While clinical prognostic markers such as the presence of metastases or tumor volume are established, little is known about the biological factors determining the risk of progression, thus precluding risk‐adapted therapeutic approaches.…”

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

“…Ewing sarcoma is a rare and highly aggressive sarcoma affecting children and young adults. Recent developments in our understanding of the molecular mechanisms underlying this disease have not yet translated into significant improvements in patients’ outcomes, and treatment has remained unchanged …”