Breakthrough Technologies Reshape the Ewing Sarcoma Molecular Landscape

Abstract

Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. At the molecular level, it is characterized by the presence of recurrent chromosomal translocations. In the last years, next-generation technologies have contributed to a more accurate diagnosis and a refined classification. Moreover, the application of these novel technologies has highlighted the relevance of intertumoral and intratumoral molecular heterogeneity and secondary genetic alterations. Furthermore, they have shown evidence that genomic features can change as the tumor disseminates and are influenced by treatment as well. Similarly, next-generation technologies applied to liquid biopsies will significantly impact patient management by allowing the early detection of relapse and monitoring response to treatment. Finally, the use of these novel technologies has provided data of great value in order to discover new druggable pathways. Thus, this review provides concise updates on the latest progress of these breakthrough technologies, underscoring their importance in the generation of key knowledge, prognosis, and potential treatment of Ewing Sarcoma.

Extracellular Vesicles: A New Source of Biomarkers in Pediatric Solid Tumors? A Systematic Review

“…Currently, risk stratification at initial diagnosis relies on imaging and molecular pathology. The first step is often FISH and/or RT-qPCR for the detection of the most common EWSR1 rearrangements ( 124 ). Prognosis depends heavily on the presence of metastatic lesions at diagnosis, which mostly presents in the lungs, bone and bone marrow ( 122 ).…”

Patterns of Translocation Testing in Patients Enrolling in a Cooperative Group Trial for Newly Diagnosed Metastatic Ewing Sarcoma

“…We show that FISH testing on primary tumor is the predominant testing type in this context, which is a cause for concern because EWSR1 translocation by FISH is not specific for the diagnosis of Ewing sarcoma as it can be seen in desmoplastic small round cell tumor and other emerging round cell sarcomas with EWSR1-non ETS fusions. 12,13 Other testing strategies were much less commonly used, with NGS of the primary tumor used in only 7 of 305 patients (2.3%). In 27 patients who had both FISH and RT-PCR performed on the primary tumor, results were discordant in 8 patients (29.6%).…”

“…In some cases (eg, desmoplastic small round cell tumor), the treatment paradigm would differ by molecular findings, 15 while in other cases (eg, an emerging group of round cell sarcoma with EWSR1-non ETS fusions) the optimal therapy may still be unknown. 12,13 It will be of interest to determine if patterns of testing evolve as NGS approaches that provide information on both fusion partners become more widely available. Likewise, RT-PCR only evaluates for prespecified translocations, and not all panels will include less common translocations that are nevertheless compatible with a molecular diagnosis of Ewing sarcoma.…”

Complete Purging of Ewing Sarcoma Metastases from Human Ovarian Cortex Tissue Fragments by Inhibiting the mTORC1 Signaling Pathway

“…The use of cell lines allowed us to perform the required culture experiments that would have been very difficult, if not impossible, to achieve with primary cancer cells. ES cancer cell lines have been used extensively for research purposes including the development of new drugs [ 51 ], characterization of drug resistance in ES [ 52 ], the effects of pharmacological treatment [ 39 ] and even for the development of clinical treatment regimens (EWING2008; ClinicalTrials.gov Identifier: NCT00987636). To study the purging effect of EVE it is essential that the ES metastases are in the appropriate microenvironment.…”