Prion-like Domains Program Ewing's Sarcoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Shorter J
PROVIDER: S-EPMC5639709 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
Prion-like domains have emerged as important drivers of neurodegenerative disease. Now, Boulay et al. establish that the translocated prion-like domain of the oncogenic EWS-FLI1 fusion protein enables phase-separation events, which inappropriately recruit chromatin-remodeling factors to elicit the aberrant transcriptional programs underlying Ewing's sarcoma. ...[more]
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Project description: Not available
| S-EPMC6984994 | biostudies-literature
Project description:Refractory and/or recurrent Ewing's sarcoma (EWS) remains a clinical challenge because the disease's resistance to therapy makes it difficult to achieve durable results with standard treatments that include chemotherapy, radiation, and surgery. Recently, insulin-like-growth-factor-1-receptor (IGF1R) antibodies have been shown to have a modest single-agent activity in EWS. Patient selection using biomarkers and understanding response and resistance mechanisms in relation to IGF1R and mammalian target of rapamycin pathways are areas of active research. Since EWS has a unique tumor-specific EWS-FLI1 t(11;22) translocation and oncogenic fusion protein, inhibition of EWS-FLI1 transcription, translation, and/or protein function may be key to eradicating EWS at the stem-cell level. Recently, a small molecule that blocks the protein-protein interaction of EWS-FLI1 with RNA helicase A has been shown in preclinical models to inhibit EWS growth. The successful application of this first-in-class protein-protein inhibitor in the clinic could become a model system for translocation-associated cancers such as EWS.
| S-EPMC2968715 | biostudies-literature
Project description:The hallmark of Ewing's sarcoma (EWS) is a translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 aberrant chimeric gene. Because EWS afflicts young patients, it stands out among the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic chemotherapy regimens produce minimal benefit in patients with metastases at presentation or those with relapsed disease. While the outcomes of chemorefractory EWS patients are generally poor, recent developments have led to the promising use of targeted therapy. Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses. However, targeted therapies in general, and these responders in particular, are faced with the ultimate conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR inhibitor-based regimens with chemotherapy in the upfront setting in newly diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in these patients. Another option is to explore novel targeted multikinase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have experienced a surge in supporting preclinical data. Drugs inhibiting the downstream targets of EWS/FLI1 are also in preclinical development. However, ultimately, the underlying biomarker correlates of resistance and response must be delineated along with ways to overcome them. Novel agents, together with integration of advances in multimodal approaches (including surgery and radiation), as well as offering targeted therapies early in the disease course represent new strategies for confronting the challenges of EWS.
| S-EPMC3893930 | biostudies-literature
Project description:A 20-year-old female presented to the Pulmonary Medicine Department with complaints of fever, left sided chest pain and progressive dyspnoea of four months duration. Radiological examination revealed a mass lesion with massive pleural effusion and rib erosion. Histopathology showed neoplastic cells with scanty cytoplasm, hyperchromatic nuclei and rosette formation suggestive of Ewing sarcoma. The rarity of this tumor and its unusual presentation prompted this report.
| S-EPMC3215445 | biostudies-other
Project description:Despite longstanding reliance upon monolayer culture for studying cancer cells, and numerous advantages from both a practical and experimental standpoint, a growing body of evidence suggests that more complex three-dimensional (3D) models are necessary to properly mimic many of the critical hallmarks associated with the oncogenesis, maintenance and spread of Ewing's sarcoma (ES), the second most common pediatric bone tumor. And as clinicians increasingly turn to biologically-targeted therapies that exert their effects not only on the tumor cells themselves, but also on the surrounding extracellular matrix, it is especially important that preclinical models evolve in parallel to reliably measure antineoplastic effects and possible mechanisms of de novo and acquired drug resistance. Herein, we highlight a number of innovative methods used to fabricate biomimetic ES tumors, encompassing both the surrounding cellular milieu and the extracellular matrix (ECM), and suggest potential applications to advance our understanding of ES biology, preclinical drug testing, and personalized medicine.
| S-EPMC4397982 | biostudies-literature
Project description:IntroductionThe parotid gland is a very rare location of Ewing's sarcoma. Its clinical and radiological manifestations are atypical. Its management is based on a multidisciplinary approach to improve prognosis and survival.DiscussionThe diagnosis of parotid Ewing's sarcoma is determined by a combination of genetic and histological criteria. Its local aggressiveness and high metastatic potential require prompt and appropriate management. Many prognostic features affect its management, the most important is the TNM staging.ConclusionLimited cases of parotid Ewing's sarcoma have been published in the literature. This small number of reported cases is the only way to study its characteristics.
| S-EPMC8080453 | biostudies-literature
Project description:BackgroundEWS-FLI1 is a chimeric ETS transcription factor that is, due to a chromosomal rearrangement, specifically expressed in Ewing's sarcoma family tumors (ESFT) and is thought to initiate the development of the disease. Previous genomic profiling experiments have identified EWS-FLI1-regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1-dependent molecular functions characterizing this aggressive cancer is lacking.Methodology/principal findingsIn this study, a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments following EWS-FLI1 knockdown in a panel of five ESFT cell lines, and on gene expression data from the same platform of 59 primary ESFT. Out of 80 normal tissues tested, mesenchymal progenitor cells (MPC) were found to fit the hypothesis that EWS-FLI1 is the driving transcriptional force in ESFT best and were therefore used as the reference tissue for the construction of the molecular function map. The interrelations of molecular pathways were visualized by measuring the similarity among annotated gene functions by gene sharing. The molecular function map highlighted distinct clusters of activities for EWS-FLI1 regulated genes in ESFT and revealed a striking difference between EWS-FLI1 up- and down-regulated genes: EWS-FLI1 induced genes mainly belong to cell cycle regulation, proliferation, and response to DNA damage, while repressed genes were associated with differentiation and cell communication.Conclusions/significanceThis study revealed that EWS-FLI1 combines by distinct molecular mechanisms two important functions of cellular transformation in one protein, growth promotion and differentiation blockage. By taking MPC as a reference tissue, a significant EWS-FLI1 signature was discovered in ESFT that only partially overlapped with previously published EWS-FLI1-dependent gene expression patterns, identifying a series of novel targets for the chimeric protein in ESFT. Our results may guide target selection for future ESFT specific therapies.
| S-EPMC2671847 | biostudies-literature
Project description:Affymetrx U95Av2 GeneChip hybridizations, RNA extracted from primary human pediatric alveolar (aRMS) and embryonal (eRMS) rhabdomyosarcoma, plus primary pediatric Ewing's sarcoma (EWS) Keywords = pediatric sarcoma Keywords = Ewing's sarcoma Keywords = rhabdomyosarcoma Keywords: other
2004-03-13 | GSE967 | GEO
Project description:We report on 12 consecutive patients with advanced/metastatic Ewing's sarcoma who were treated as a separate cohort of a phase 1 trial of FANG autologous immunotherapy (1?×?10(6)-2.5?×?10(7) cells/intradermal injection each month for minimum 4 months). Safety and clinical response were monitored. Patient immune response to unmodified autologous tumor cells was assessed by gamma interferon-enzyme-linked immunospot (?IFN-ELISPOT) assay using peripheral blood mononuclear cells from baseline (pretreatment) and multiple postvaccination time points. None of the 12 patients (47 vaccinations) developed grade 2/3/4 drug-related toxicity. Median product release granulocyte-macrophage colony-stimulating factor expression was 1,941 pg/10(6) cells, and TGF?1and TGF?2 knockdown were 99 and 100%, respectively. Eight patients were assessed for ELISPOT response to autologous tumor cells at baseline and all (100%) were negative. In contrast, follow-up ELISPOT response at month 1 or month 4 (one patient) after FANG was positive in all eight patients. One patient achieved a partial tumor response (38% tumor reduction, RECIST 1.1). The Kaplan-Meier estimated survival of these 12 patients at 1 year was 75%. In this phase 1 study in patients with Ewing's sarcoma, FANG immunotherapy was well tolerated, elicited a tumor-specific systemic immune response in all patients, and was associated with favorable 1-year survival. Further clinical testing is indicated.
| S-EPMC4817748 | biostudies-literature
Project description:BackgroundLong non-coding RNAs (lncRNAs) are a class of non-coding RNAs with unique characteristics. These RNA can regulate cancer cells' survival, proliferation, invasion, metastasis, and angiogenesis and are potential diagnostic and prognostic markers. We identified a seven-lncRNA signature related to the overall survival (OS) of patients with Ewing's sarcoma (EWS).MethodsWe used an expression profile from the Gene Expression Omnibus (GEO) database as a training cohort to screen out the OS-associated lncRNAs in EWS and further established a seven-lncRNA signature using univariate Cox regression, the least absolute shrinkage, and selection operator (LASSO) regression analysis. The prognostic lncRNA signature was validated in an external dataset from the International Cancer Genome Consortium (ICGC) as a validation cohort.ResultsWe obtained 10 survival-related lncRNAs from the Kaplan-Meier and ROC curve analysis (log-rank test P < 0.05; AUC >0.6). Univariate Cox regression and LASSO regression analyses confirmed seven key lncRNAs and we established a lncRNA signature to predict an EWS prognosis. EWS patients in the training cohort were categorized into a low-risk group or a high-risk group based on their median risk score. The high-risk group's survival time was significantly shorter than the low-risk group's. This seven-lncRNA signature was further confirmed by the validation cohort. The area under the curve (AUC) for this lncRNA signature was up to 0.905 in the training group and 0.697 in the 3-year validation group. The nomogram's calibration curves demonstrated that EWS probability in the two cohorts was consistent between the nomogram prediction and actual observation.ConclusionWe screened a seven-lncRNA signature to predict the EWS patients' prognosis. Our findings provide a new reference for the current prognostic evaluation of EWS and new direction for the diagnosis and treatment of EWS.
| S-EPMC8214847 | biostudies-literature