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Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 21045

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Prof. Dr. Stefan Burdach

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Translational Pediatric Cancer Research Action, Institute of Pathology and Department of Pediatrics, TUM School of Medicine, Technical University of Munich, 80804 Munich, Germany
Interests: pediatric oncology; pediatric sarcomas; Ewing sarcoma; pediatric ALL; epigenetics; T cell immunology; immunometabolism; immunotherapy; cellular therapies; targeted therapies

Prof. Dr. Uta Dirksen

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Guest Editor

Pediatrics III, West German Cancer Centre, University Hospital Essen, 45147 Essen, Germany
Interests: translational research in bone sarcoma of young people; academia initiated clinical trials in bone sarcoma of young people; late effects and prevention

Prof. Dr. Poul H. Sorensen

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Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
Interests: stress signaling and metabolic adaptation; selective mRNA translation and metastatic capacity; EWS-ETS fusion proteins and how they confer stress adaptation

Special Issue Information

Dear Colleagues,

Ewing sarcomas are characterized by unique ews/ets translocations, which constitute prototypic oncogenic drivers. However, these oncofusions do not determine clinical biology and outcome. Patient fate is almost exclusively determined by metastasis and both the high propensity and the complex process of spread are far from being completely understood. Ewing sarcomas are amongst childhood cancers with a low mutational rate, making reliable biomarkers elusive. Mutation rates increase, however, with relapse and cumulative mutagenic therapy exposure. However, a silent tumor genome generally limits targeted therapy approaches, which applies particularly for Ewing sarcoma. Precision oncology approaches, nevertheless, aim at enhancing the therapeutic index of conventional chemotherapy with novel small molecules targeting epigenetics, metabolism and the stress response.

Albeit their genome is generally silent, Ewing sarcomas reactivate endogenous retroelements. Their activation is linked to a particular inflammatory response and a prometastatic modulation of the microenvironment. On the other hand, Ewing sarcomas are characterized, at least in most cases, by immune inertia, i.e., a scarcity of T cell infiltrates and a predominance of immunosuppressive myeloid signatures (M0/M2), leading to the antagonistic processes of inflammation and immunosuppression. These suppressive myeloid cells shield the tumor against adaptive immune attack, hampering the efficacy of chimeric antigen receptor or T cell receptor transgenic T cells. Overcoming these immunosuppressive mechanisms may enhance immunotherapeutic efficacy. One approach in this regard is the utilization of oncolytic viruses, genetically engineered to depend on their lytic cycle from metastatic drivers. They can induce immunogenic cell death and, particularly when in combination with cell cycle inhibitors, do have the potential to also overcome barriers to immunotherapy in Ewing sarcoma.

Prof. Dr. Stefan Burdach
Prof. Dr. Uta Dirksen
Prof. Dr. Poul H. Sorensen
Guest Editors

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11 pages, 1630 KiB

Open AccessCommunication

Routine EWS Fusion Analysis in the Oncology Clinic to Identify Cancer-Specific Peptide Sequence Patterns That Span Breakpoints in Ewing Sarcoma and DSRCT

by Peter M. Anderson, Zheng Jin Tu, Scott E. Kilpatrick, Matteo Trucco, Rabi Hanna and Timothy Chan

Cancers 2023, 15(5), 1623; https://doi.org/10.3390/cancers15051623 - 06 Mar 2023

Cited by 2 | Viewed by 1779

Abstract

(1) Background: EWS fusion genes are associated with Ewing sarcoma and other Ewing family tumors including desmoplastic small round tumor, DSRCT. We utilize a clinical genomics workflow to reveal real-world frequencies of EWS fusion events, cataloging events that are similar, or divergent at the EWS breakpoint. (2) Methods: EWS fusion events from our next-generation sequencing panel (NGS) samples were first sorted by breakpoint or fusion junctions to map out the frequency of breakpoints. Fusion results were illustrated as in-frame fusion peptides involving EWS and a partner gene. (3) Results: From 2471 patient pool samples for fusion analysis at the Cleveland Clinic Molecular Pathology Laboratory, we identified 182 fusion samples evolved with the EWS gene. They are clustered in several breakpoints: chr22:29683123 (65.9%), and chr22:29688595 (2.7%). About 3/4 of Ewing sarcoma and DSRCT tumors have an identical EWS breakpoint motif at Exon 7 (SQQSSSYGQQ-) fused to a specific part of FLI1 (NPSYDSVRRG or-SSLLAYNTSS), ERG (NLPYEPPRRS), FEV (NPVGDGLFKD) or WT1 (SEKPYQCDFK). Our method also worked with Caris transcriptome data, too. Our primary clinical utility is to use this information to identify neoantigens for therapeutic purposes. (4) Conclusions and future perspectives: our method allows interpretation of what peptides result from the in-frame translation of EWS fusion junctions. These sequences, coupled with HLA-peptide binding data, are used to identify potential sequences of cancer-specific immunogenic peptides for Ewing sarcoma or DSRCT patients. This information may also be useful for immune monitoring (e.g., circulating T-cells with fusion-peptide specificity) to detect vaccine candidates, responses, or residual disease. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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35 pages, 6690 KiB

Open AccessArticle

Exploiting the Stemness and Chemoresistance Transcriptome of Ewing Sarcoma to Identify Candidate Therapeutic Targets and Drug-Repurposing Candidates

by Elizabeth Ann Roundhill, Pan Pantziarka, Danielle E. Liddle, Lucy A. Shaw, Ghadeer Albadrani and Susan Ann Burchill

Cancers 2023, 15(3), 769; https://doi.org/10.3390/cancers15030769 - 26 Jan 2023

Cited by 2 | Viewed by 1898

Abstract

Outcomes for most patients with Ewing sarcoma (ES) have remained unchanged for the last 30 years, emphasising the need for more effective and tolerable treatments. We have hypothesised that using small-molecule inhibitors to kill the self-renewing chemotherapy-resistant cells (Ewing sarcoma cancer stem-like cells; ES-CSCs) responsible for progression and relapse could improve outcomes and minimise treatment-induced morbidities. For the first time, we demonstrate that ABCG1, a potential oncogene in some cancers, is highly expressed in ES-CSCs independently of CD133. Using functional models, transcriptomics and a bespoke in silico drug-repurposing pipeline, we have prioritised a group of tractable small-molecule inhibitors for further preclinical studies. Consistent with the cellular origin of ES, 21 candidate molecular targets of pluripotency, stemness and chemoresistance were identified. Small-molecule inhibitors to 13 of the 21 molecular targets (62%) were identified. POU5F1/OCT4 was the most promising new therapeutic target in Ewing sarcoma, interacting with 10 of the 21 prioritised molecular targets and meriting further study. The majority of small-molecule inhibitors (72%) target one of two drug efflux proteins, p-glycoprotein (n = 168) or MRP1 (n = 13). In summary, we have identified a novel cell surface marker of ES-CSCs and cancer/non-cancer drugs to targets expressed by these cells that are worthy of further preclinical evaluation. If effective in preclinical models, these drugs and drug combinations might be repurposed for clinical evaluation in patients with ES. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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19 pages, 2762 KiB

Open AccessArticle

Correlation of Transcriptomics and FDG-PET SUVmax Indicates Reciprocal Expression of Stemness-Related Transcription Factor and Neuropeptide Signaling Pathways in Glucose Metabolism of Ewing Sarcoma

by Carolin Prexler, Marie Sophie Knape, Janina Erlewein-Schweizer, Wolfgang Roll, Katja Specht, Klaus Woertler, Wilko Weichert, Irene von Luettichau, Claudia Rossig, Julia Hauer, Guenther H. S. Richter, Wolfgang Weber and Stefan Burdach

Cancers 2022, 14(23), 5999; https://doi.org/10.3390/cancers14235999 - 05 Dec 2022

Cited by 2 | Viewed by 1529

Abstract

Background: In Ewing sarcoma (EwS), long-term treatment effects and poor survival rates for relapsed or metastatic cases require individualization of therapy and the discovery of new treatment methods. Tumor glucose metabolic activity varies significantly between patients, and FDG-PET signals have been proposed as prognostic factors. However, the biological basis for the generally elevated but variable glucose metabolism in EwS is not well understood. Methods: We retrospectively included 19 EwS samples (17 patients). Affymetrix gene expression was correlated with maximal standardized uptake value (SUVmax) using machine learning, linear regression modelling, and gene set enrichment analyses for functional annotation. Results: Expression of five genes correlated (MYBL2, ELOVL2, NETO2) or anticorrelated (FAXDC2, PLSCR4) significantly with SUVmax (adjusted p-value ≤ 0.05). Additionally, we identified 23 genes with large SUVmax effect size, which were significantly enriched for “neuropeptide Y receptor activity (GO:0004983)” (adjusted p-value = 0.0007). The expression of the members of this signaling pathway (NPY, NPY1R, NPY5R) anticorrelated with SUVmax. In contrast, three transcription factors associated with maintaining stemness displayed enrichment of their target genes with higher SUVmax: RNF2, E2F family, and TCF3. Conclusion: Our large-scale analysis examined comprehensively the correlations between transcriptomics and tumor glucose utilization. Based on our findings, we hypothesize that stemness may be associated with increased glucose uptake, whereas neuroectodermal differentiation may anticorrelate with glucose uptake. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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13 pages, 1221 KiB

Open AccessArticle

Ewing Sarcoma as Secondary Malignant Neoplasm—Epidemiological and Clinical Analysis of an International Trial Registry

by Stefan K. Zöllner, Katja L. Kauertz, Isabelle Kaiser, Maximilian Kerkhoff, Christiane Schaefer, Madita Tassius, Susanne Jabar, Heribert Jürgens, Ruth Ladenstein, Thomas Kühne, Lianne M. Haveman, Michael Paulussen, Andreas Ranft and Uta Dirksen

Cancers 2022, 14(23), 5935; https://doi.org/10.3390/cancers14235935 - 30 Nov 2022

Cited by 1 | Viewed by 1402

Abstract

Ewing sarcoma (EwS) is the second most common bone and soft tissue tumor, affecting primarily adolescents and young adults. Patients with secondary EwS are excluded from risk stratification in several studies and therefore do not benefit from new therapies. More knowledge about patients with EwS as secondary malignant neoplasms (SMN) is needed to identify at-risk patients and adapt follow-up strategies. Epidemiology, clinical characteristics, and survival analyses of EwS as SMN were analyzed in 3844 patients treated in the last three consecutive international EwS trials, EICESS 92, Euro-E.W.I.N.G. 99, and EWING 2008. Forty-two cases of EwS as SMN (approximately 1.1% of all patients) were reported, preceded by a heterogeneous group of malignancies, mainly acute lymphoblastic leukemias (n = 7) and lymphomas (n = 7). Three cases of EwS as SMN occurred in the presumed radiation field of the primary tumor. The median age at diagnosis of EwS as SMN was 19.4 years (range, 5.9–72) compared with 10.8 years (range, 0.9–51.2) for primary EwS. The median interval between first malignancy and EwS diagnosis was 7.4 years. The 3-year overall survival (OS)/event-free survival (EFS) was 0.69 (SE = 0.09)/0.53 (SE = 0.10) for localized patients and 0.36 (SE = 0.13)/0.29 (SE = 0.12) for metastatic patients (OS: p = 0.02; EFS: p = 0.03). Survival in patients with EwS as SMN did not differ between hematologic or solid primary malignancies. EwS as SMN is rare; however, survival is similar to that of primary EwS, and its risk-adjusted treatment should be curative, especially in localized patients. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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15 pages, 726 KiB

Open AccessArticle

Secondary Malignancies after Ewing Sarcoma—Epidemiological and Clinical Analysis of an International Trial Registry

by Isabelle Kaiser, Katja Kauertz, Stefan K. Zöllner, Wolfgang Hartmann, Thorsten Langer, Heribert Jürgens, Andreas Ranft and Uta Dirksen

Cancers 2022, 14(23), 5920; https://doi.org/10.3390/cancers14235920 - 30 Nov 2022

Cited by 3 | Viewed by 1610

Abstract

Ewing sarcoma (EwS) represents highly aggressive bone and soft tissue tumors that require intensive treatment by multi-chemotherapy, surgery and/or radiotherapy. While therapeutic regimens have increased survival rates, EwS survivors face long-term sequelae that include secondary malignant neoplasms (SMNs). Consequently, more knowledge about EwS patients who develop SMNs is needed to identify high-risk patients and adjust follow-up strategies. We retrospectively analyzed data from 4518 EwS patients treated in five consecutive EwS trials from the Cooperative Ewing Sarcoma Study (CESS) group. Ninety-six patients developed SMNs after primary EwS, including 53 (55.2%) with solid tumors. The latency period between EwS and the first SMN was significantly longer for the development of solid SMNs (median: 8.4 years) than for hematologic SMNs (median: 2.4 years) (p < 0.001). The cumulative incidence (CI) of SMNs in general increased over time from 0.04 at 10 years to 0.14 at 30 years; notably, the specific CI for hematologic SMNs remained stable over the different decades, whereas for solid SMNs it gradually increased over time and was higher for metastatic patients than in localized EwS patients (20 years: 0.14 vs. 0.06; p < 0.01). The clinical characteristics of primary EwS did not differ between patients with or without SMNs. All EwS patients received multi-chemotherapy with adjuvant radiotherapy in 77 of 96 (80.2%) patients, and the use of radiation doses ≥ 60 Gy correlated with the occurrence of SMNs. The survival rate after SMNs was 0.49, with a significantly better outcome for solid SMNs compared with hematologic SMNs (3 years: 0.70 vs. 0.24, respectively; p < 0.001). The occurrence of SMNs after EwS remains a rare event but requires a structured follow-up system because it is associated with high morbidity and mortality. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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11 pages, 930 KiB

Open AccessArticle

C-Reactive Protein Pretreatment-Level Evaluation for Ewing’s Sarcoma Prognosis Assessment—A 15-Year Retrospective Single-Centre Study

by Sarah Consalvo, Florian Hinterwimmer, Norbert Harrasser, Ulrich Lenze, Georg Matziolis, Rüdiger von Eisenhart-Rothe and Carolin Knebel

Cancers 2022, 14(23), 5898; https://doi.org/10.3390/cancers14235898 - 29 Nov 2022

Cited by 2 | Viewed by 1210

Abstract

Background: A pathological/inflamed cellular microenvironment state is an additional risk factor for any cancer type. The importance of a chronic inflammation state in most diffuse types of tumour has already been analysed, except for in Ewing’s sarcoma. It is a highly malignant blue round cell tumour, with 90% of cases occurring in patients aged between 5 and 25 years. Worldwide, 2.9 out of 1,000,000 children per year are affected by this malignancy. The aim of this retrospective study was to analyse the role of C-reactive protein (CRP) as a prognostic factor for Ewing’s sarcomas. Methods: This retrospective study at Klinikum rechts der Isar included 82 patients with a confirmed Ewing’s sarcoma diagnosis treated between 2004 and 2019. Preoperative CRP determination was assessed in mg/dL with a normal value established as below 0.5 mg/dL. Disease-free survival time was calculated as the time between the initial diagnosis and an event such as local recurrence or metastasis. Follow-up status was described as death of disease (DOD), no evidence of disease (NED) or alive with disease (AWD). The exclusion criteria of this study included insufficient laboratory values and a lack of information regarding the follow-up status or non-oncological resection. Results: Serum CRP levels were significantly different in patients with a poorer prognosis (DOD) and in patients who presented distant metastasis (p = 0.0016 and p = 0.009, respectively), whereas CRP levels were not significantly different in patients with local recurrence (p = 0.02). The optimal breakpoint that predicted prognosis was 0.5 mg/dL, with a sensitivity of 0.76 and a specificity of 0.74 (AUC 0.81). Univariate CRP analysis level >0.5 mg/dL revealed a hazard ratio of 9.5 (95% CI 3.5–25.5). Conclusions: In Ewing’s sarcoma cases, we consider a CRP pretreatment value >0.5 mg/dL as a sensitive prognostic risk factor indication for distant metastasis and poor prognosis. Further research with more data is required to determine more sensitive cutoff levels. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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20 pages, 4017 KiB

Open AccessArticle

Identification of Factors Driving Doxorubicin-Resistant Ewing Tumor Cells to Survival

by Semyon Yakushov, Maxim Menyailo, Evgeny Denisov, Irina Karlina, Viktoria Zainullina, Kirill Kirgizov, Olga Romantsova, Peter Timashev and Ilya Ulasov

Cancers 2022, 14(22), 5498; https://doi.org/10.3390/cancers14225498 - 09 Nov 2022

Cited by 4 | Viewed by 1730

Abstract

Background: Ewing sarcoma (ES) cells exhibit extreme plasticity that contributes to the cell’s survival and recurrence. Although multiple studies reveal various signaling pathways mediated by the EWSR1/FLI1 fusion, the specific transcriptional control of tumor cell resistance to doxorubicin is unknown. Understanding the molecular hubs that contribute to this behavior provides a new perspective on valuable therapeutic options against tumor cells. Methods: Single-cell RNA sequencing and LC-MS/MS-based quantitative proteomics were used. Results: A goal of this study was to identify protein hubs that would help elucidate tumor resistance which prompted ES to relapse or metastasize. Several differentially expressed genes and proteins, including adhesion, cytoskeletal, and signaling molecules, were observed between embryonic fibroblasts and control and doxorubicin-treated tumor cell lines. While several cancer-associated genes/proteins exhibited similar expression across fibroblasts and non-treated cells, upregulation of some proteins belonging to metabolic, stress response, and growth pathway activation was uniquely observed in doxorubicin-treated sarcoma cells, respectively. The novel information on differentially expressed genes/proteins provides insights into the biology of ES cells, which could help elucidate mechanisms of their recurrence. Conclusions: Collectively, our results identify a novel role of cellular proteins in contributing to tumor cell resistance and escape from doxorubicin therapy and contributing to ES progression. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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18 pages, 3091 KiB

Open AccessArticle

T Cells Directed against the Metastatic Driver Chondromodulin-1 in Ewing Sarcoma: Comparative Engineering with CRISPR/Cas9 vs. Retroviral Gene Transfer for Adoptive Transfer

by Busheng Xue, Kristina von Heyking, Hendrik Gassmann, Mansour Poorebrahim, Melanie Thiede, Kilian Schober, Josef Mautner, Julia Hauer, Jürgen Ruland, Dirk H. Busch, Uwe Thiel and Stefan E. G. Burdach

Cancers 2022, 14(22), 5485; https://doi.org/10.3390/cancers14225485 - 08 Nov 2022

Cited by 2 | Viewed by 1735

Abstract

Ewing sarcoma (EwS) is a highly malignant sarcoma of bone and soft tissue with early metastatic spread and an age peak in early puberty. The prognosis in advanced stages is still dismal, and the long-term effects of established therapies are severe. Efficacious targeted therapies are urgently needed. Our previous work has provided preliminary safety and efficacy data utilizing T cell receptor (TCR) transgenic T cells, generated by retroviral gene transfer, targeting HLA-restricted peptides on the tumor cell derived from metastatic drivers. Here, we compared T cells engineered with either CRISPR/Cas9 or retroviral gene transfer. Firstly, we confirmed the feasibility of the orthotopic replacement of the endogenous TCR by CRISPR/Cas9 with a TCR targeting our canonical metastatic driver chondromodulin-1 (CHM1). CRISPR/Cas9-engineered T cell products specifically recognized and killed HLA-A*02:01+ EwS cell lines. The efficiency of retroviral transduction was higher compared to CRISPR/Cas9 gene editing. Both engineered T cell products specifically recognized tumor cells and elicited cytotoxicity, with CRISPR/Cas9 engineered T cells providing prolonged cytotoxic activity. In conclusion, T cells engineered with CRISPR/Cas9 could be feasible for immunotherapy of EwS and may have the advantage of more prolonged cytotoxic activity, as compared to T cells engineered with retroviral gene transfer. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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Review

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20 pages, 1149 KiB

Open AccessEditor’s ChoiceReview

Current State of Immunotherapy and Mechanisms of Immune Evasion in Ewing Sarcoma and Osteosarcoma

by Valentina Evdokimova, Hendrik Gassmann, Laszlo Radvanyi and Stefan E. G. Burdach

Cancers 2023, 15(1), 272; https://doi.org/10.3390/cancers15010272 - 30 Dec 2022

Cited by 14 | Viewed by 3161

Abstract

We argue here that in many ways, Ewing sarcoma (EwS) is a unique tumor entity and yet, it shares many commonalities with other immunologically cold solid malignancies. From the historical perspective, EwS, osteosarcoma (OS) and other bone and soft-tissue sarcomas were the first types of tumors treated with the immunotherapy approach: more than 100 years ago American surgeon William B. Coley injected his patients with a mixture of heat-inactivated bacteria, achieving survival rates apparently higher than with surgery alone. In contrast to OS which exhibits recurrent somatic copy-number alterations, EwS possesses one of the lowest mutation rates among cancers, being driven by a single oncogenic fusion protein, most frequently EWS-FLI1. In spite these differences, both EwS and OS are allied with immune tolerance and low immunogenicity. We discuss here the potential mechanisms of immune escape in these tumors, including low representation of tumor-specific antigens, low expression levels of MHC-I antigen-presenting molecules, accumulation of immunosuppressive M2 macrophages and myeloid proinflammatory cells, and release of extracellular vesicles (EVs) which are capable of reprogramming host cells in the tumor microenvironment and systemic circulation. We also discuss the vulnerabilities of EwS and OS and potential novel strategies for their targeting. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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28 pages, 2331 KiB

Open AccessReview

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies

by Sara Sánchez-Molina, Elisabet Figuerola-Bou, Víctor Sánchez-Margalet, Luis de la Cruz-Merino, Jaume Mora, Enrique de Álava Casado, Daniel José García-Domínguez and Lourdes Hontecillas-Prieto

Cancers 2022, 14(21), 5473; https://doi.org/10.3390/cancers14215473 - 07 Nov 2022

Cited by 4 | Viewed by 3612

Abstract

Ewing Sarcoma (EWS) is an aggressive bone and soft tissue tumor that mainly affects children, adolescents, and young adults. The standard therapy, including chemotherapy, surgery, and radiotherapy, has substantially improved the survival of EWS patients with localized disease. Unfortunately, this multimodal treatment remains elusive in clinics for those patients with recurrent or metastatic disease who have an unfavorable prognosis. Consistently, there is an urgent need to find new strategies for patients that fail to respond to standard therapies. In this regard, in the last decade, treatments targeting epigenetic dependencies in tumor cells and the immune system have emerged into the clinical scenario. Additionally, recent advances in nanomedicine provide novel delivery drug systems, which may address challenges such as side effects and toxicity. Therefore, therapeutic strategies stemming from epigenetics, immunology, and nanomedicine yield promising alternatives for treating these patients. In this review, we highlight the most relevant EWS preclinical and clinical studies in epigenetics, immunotherapy, and nanotherapy conducted in the last five years. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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