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  • Of all ES cases approximately are metastatic diseases

    2021-04-07

    Of all ES cases, approximately 26–28% are metastatic diseases at diagnosis with the remainder being localized disease [14]. Instituting a systemic chemotherapy regimen in combination with surgery and/or radiotherapy has significantly increased the survival of patients with localized disease. The 5-year survival rate was less than 15% before chemotherapy became available, 44% for patients in the decade between 1973 and 1982, while for the decade between 1993 and 2004, survival rates from recently completed large cooperative groups trials (such as AWES-0031 and EURO-Ewing 99) report survival rates of approximately 70% [14], [15]. Unfortunately, the prognosis of patients with metastatic ES remains dismal, with 5-year survival rates of approximately 20–30% [16]. In addition to standard of care treatment modalities, which will clearly continue to have value, novel therapies have been tested in clinical trials with the hopes of increasing survival and clinical benefits have been achieved in some patients. Compared to conventional chemotherapies, targeted therapies are specifically directed to sanguinarine associated with tumorigenesis and tumor progression of ES. These include insulin-like growth factor 1 receptor (IGF-1R), mammalian target of rapamycin (mTOR), tyrosine kinases such as platelet-derived growth factor receptor (PDGFR), KIT, epidermal growth factor receptor (EGFR), vascular growth factor receptors (VEGFRs), Aurora A, poly ADP ribose polymerase 1 (PARP1), and GD2, all of which are in phase I and II clinical testing (Table 2, Table 3) [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. Therapies targeting other proteins such as EWS-FLI1 and CD99 are in preclinical testing and may be promising targets for novel therapies. In addition, new molecules have been identified in mechanistic studies and may be clinically applicable. A better understanding of the underlying mechanism of ES and associated molecular aberrations will greatly aid in the discovery of new molecular targets and the development of targeted therapies.
    Molecular targets for directed therapy
    Challenges of Targeted therapies The first challenge stems from the disconnection between preclinical studies and human clinical trial results. Frequently, clinical trials showed low efficacy despite promising results in preclinical trials. Several factors are behind this. First, the origin of ES is not precisely known, which adds difficulty in understanding the transformation from normal cells to tumor [131]. Second, it is difficult to build in vitro and animal models for preclinical testing. Two-dimensional monolayer cells have been used predominantly in in vitro studies while several studies have shown phenotype and drug sensitivity changes in three-dimensional cultures using the same cell line [132]. In addition, there are no spontaneous ES animal models and genetically-engineered ones fail to result in ES-like tumors, limiting the predictive value of preclinical animal studies [133]. Third, most of the tested targetable proteins play a role in initial tumor growth and hence their inhibition may be clinically helpful in early disease. However, clinical trials are usually performed on advanced stage tumors, in which targeting these proteins may not be sufficient to inhibit the tumorigenesis process. Last but not least, potential and attractive targets, such as AKT, still do not have a clinically useful and stable inhibitor. The second challenge is to identify biomarkers that accurately forecast treatment outcome [134]. Our institutional experience from several advanced cancers suggests that therapies matching underlying actionable somatic mutations can improve outcomes compared to unmatched therapies [135]. Unfortunately, this strategy has not yet been successfully adapted for the treatment of ES. Recently published studies utilizing next-generation sequencing technologies have shown that significant fraction of ES patients have recurrent genetic mutations other than EWSR1-ETS fusion gene product, particularly STAG2 mutations, which may lead to chromosomal structural defect and aneuploidy [100], [101], [102]. Crompton et al. suggested that relapsed disease is genetically different from disease at diagnosis, which increases the genomic complexity of the disease [101].