RARE DISEASE
Skeletal Ewing sarcoma
Skeletal Ewing sarcoma
Skeletal Ewing sarcoma
Synonyms: Osseous Ewing sarcoma
Synonyms: Osseous Ewing sarcoma
Synonyms: Osseous Ewing sarcoma
Drug discovery
20
drugs
With orphan designations
Overview
Skeletal Ewing sarcoma is a rare, aggressive bone malignancy characterized by chromosomal translocations (e.g., EWSR1-FLI1), primarily affecting children and adolescents. Most common in long bones (femur, pelvis, ribs), it often presents with pain, swelling, and pathological fractures. Treatment involves multimodal chemotherapy, surgery, and/or radiotherapy. Despite advancements, metastatic or recurrent disease carries a poor prognosis (5-year survival <30%). Survivors face significant chronic health burdens, including cardiovascular and musculoskeletal complications [1][4][15].
Burden
Survival: 70% 5-year survival in localized cases vs. <30% for metastatic disease [3][5][15].
Chronic morbidity: 30% hypertension, 14% cardiomyopathy, and musculoskeletal impairments in survivors [4].
Late effects: Radiation-linked second malignancies; neurocognitive deficits linked to chronic condition burden [4][17].
Therapies
Chemotherapy: Neoadjuvant/adjuvant regimens (e.g., vincristine, doxorubicin, cyclophosphamide) to shrink tumors and target micrometastases [1][5][16].
Local control: Surgery (limb-salvage preferred) ± radiation, guided by tumor resectability and functional impact [1][12][17].
Investigational: Targeted therapies (e.g., EWSR1-FLI1 inhibitors) and immunotherapies in clinical trials for refractory/metastatic disease [3][8][19].
Categories: rare bone diseases, rare neoplastic diseases
Research Papers
811 drug discovery papers about Skeletal Ewing sarcoma, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
811 drug discovery papers about Skeletal Ewing sarcoma, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-04-03 | Abstract 5426: Anatomic origins of primary skeletal tumors effect metastatic and prognostic behaviors.
Abstract Introduction: This study investigates the histology of nonmetastatic primary skeletal tumors related to their anatomic origin and its influence on 5-year survival outcomes. Methodology: Deidentified patient data were obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Inclusion criteria included: (1) diagnosis of a primary bone cancer with anatomical location of origin, classified using ICD-O-3 anatomic site codes; (2) documented absence of metastasis to the brain, lung, liver, or bone; (3) cause-specific death and survival duration; and (4) available histology codes. Patients were stratified by primary tumor location and histologic sub-type. Kaplan-Meier survival curves were used to estimate survival, and group differences were assessed with pairwise log-rank tests. A p-value <0.05 was considered statistically significant. Results: The top five most common nonmetastatic skeletal tumors by histology are Chondrosarcoma, Osteosarcoma, Chondroma, Ewing Sarcoma, and Diffuse Large B-Cell Lymphoma (DLBCL). The tumor location distribution and 5-year survival for each histological subclass are outlined in Table 1. Conclusion: The differences in anatomic origin of primary bone tumors when controlled for histologic category influences patient mortality. There are distinct differences in overall survival compared among origin sites, signifying a location-based influence on disease severity and survival. The knowledge of anatomic origin differences of survival of various histologic categories of bone cancer can improve clinical decision making and create more accurate, locational based planning when looking at prognosis and disease progression. Citation Format: Matthew Duazo, Aayush Bhatawadekar, Dillon Pekoff, Maria Plummer, Brian Beatty, . Anatomic origins of primary skeletal tumors effect metastatic and prognostic behaviors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5426.
2025-12-26 | Aggressive Ewing Sarcoma of the Mandible in a Child: A Case Report
Ewing sarcoma is a highly aggressive malignant bone tumor which most commonly arises in the long bones and pelvis of adolescents and young adults. Craniofacial involvement, particularly of the mandible, is extremely rare and may mimic odontogenic or inflammatory lesions, leading to diagnostic delay. We report the case of a 14-year-old girl with histologically confirmed Ewing sarcoma of the left mandible. Clinical and initial radiological findings suggested an aggressive mandibular lesion with locoregional extension. For comprehensive baseline evaluation, an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was performed. It demonstrated intense metabolic activity of the mandibular mass, consistent with high tumor aggressiveness, while excluding cervical, thoracic, abdominal, and skeletal metastases. This case underlines the crucial role of 18F-FDG PET/CT not only in the initial staging of Ewing sarcoma but also in the differential diagnosis of atypical mandibular swellings in children and adolescents. By combining functional and anatomical data, PET/CT improves diagnostic confidence, guides therapeutic planning, and contributes to prognostic assessment in such uncommon presentations.
2025-11-14 | [Reconstruction of primary malignant bone tumors in children: Do we really need to change our methods?].
Primary bone tumors in children are almost exclusively represented by osteosarcomas and Ewing sarcomas. They mainly affect the limbs, particularly the lower limbs. It is estimated that there are approximately 250 new cases per year. While the initial goal is survival, the question of reconstruction quickly follows. The aim of reconstruction is to avoid amputation, ensure functional outcomes, and, if possible, support ongoing growth in these children. For a long time, free fibula transfer was the first choice, as it allowed for the use of a vascularized bone whose shape was well-suited for limb reconstruction. Later, the induced membrane technique, also known as the Masquelet technique, was introduced. New radiotherapy protocols led to a preference for this latter technique. One of the arguments was that the risk of nonunion or delayed union would be too high with fibula grafts. So much so that, in our experience, no free fibula transfers were performed between 2015 and 2020. However, the analysis of the data from our series shows quite the opposite and does not support the superiority of the Masquelet technique (quite the contrary). Moreover, the fibula remains irreplaceable in certain indications (joint reconstruction, growth plate reconstruction, bi- or trifoliate graft reconstruction, etc.). Therefore, based on the analysis of our experience, the free fibula graft does not appear to be inferior in the specific context of bone reconstruction in children following malignant tumor resection.
2025-11-11 | Evaluation of the results of combined free vascularized fibular graft and pasteurized tumor segment for the reconstruction of intercalary femoral defects following tumor resection.
the reconstruction of intercalary femoral defects after tumour resection is challenging. We have evaluated the clinical, functional, and oncological results of using free vascularized fibular graft combined with preserved pasteurized tumour segment. this study was retrospective in nature and included 12 patients [eight males and four females]. The mean age was 21.3 years ± 11.3. The diagnoses of the patients were osteosarcoma (Five cases) and Ewing's sarcoma (seven cases). The resection was wide local excision, and the defect was reconstructed using combined free vascularized fibular graft and pasteurized tumour segment. the mean time to union was 7.1 ± 1.9 months while the mean time to full weight bearing was 12 ± 1.8 months. The mean size of skeletal defect was 17.7 cm ± 1.92. The mean duration of surgery was 12.1 h ± 1.88. Nonunion occurred in four cases, stress fractures occurred in two cases and metal failure occurred in one case. the combined technique of using free vascularized fibular graft and pasteurized tumour segment for intercalary femoral defects following tumour resection is a valuable technique with accepted complications and good results.
2025-10-01 | Comparison of Biological Reconstruction After Resection of Proximal Humerus Bone Sarcomas in Pediatric Patients
Background: The aim of this study was to investigate the clinical outcomes and complications of vascularized fibular epiphyseal transfer (VFET) and clavicle pro humero (CPH) for proximal humeral reconstruction after primary sarcoma resection in skeletally immature patients. Patients and Methods: This retrospective case-control study included 29 skeletally immature patients (18 male patients, 11 female patients) with primary bone sarcomas who were treated between January 2009 and June 2023 at Beijing Jishuitan Hospital. The average age was 9.4 ± 2.8 years (range, 5-14), and the pathological type included osteosarcoma (25) and Ewing sarcoma (4). We compared the graft survival, function, and complication rate between the VFET group and the CPH group. Results: The 2-year and 5-year overall survival rates for the VFET group and CPH group were 94%, 75%, 86%, and 55%, respectively. The 2-year and 5-year revision-free survival for the VFET group and CPH group were 77%, 61%, 75%, and 37%, respectively. At the final follow-up, the mean MSTS-93 score in the VFET group was 82% (67%-97%), while the mean MSTS-93 score in the CPH group was 79% (73%-96%, p > 0.05). The incidence of mechanical complications was significantly higher in the CPH group (88%, 7/8) than that in the VFET group (52%, 11/21) (p = 0.036). The mean difference in upper limb length in the VFET group was 5.0 ± 2.9 cm and 10.2 ± 4.2 cm in the CPH group (p = 0.003). Conclusions: We suggest that vascularized fibular epiphyseal transfer may be considered as a promising biological reconstruction option for pediatric patients with proximal humeral osteosarcoma who have a longer life expectancy. For institutions lacking the necessary microsurgical techniques, clavicle pro humero reconstruction remains a relatively simple and feasible alternative reconstruction option. Level of Evidence: Level III Case-control study. See Instructions for Authors for a complete description of levels of evidence.
small molecules
2026-03-02 | Primary breast Ewing sarcoma in a young adult: diagnostic challenges and neoadjuvant chemotherapy success<b></b>
Extra-skeletal Ewing Sarcoma (EES) is a malignant soft-tissue tumor morphologically indistinguishable from osseous Ewing Sarcoma (ES). The Ewing family includes ES, EES, Askin tumor, and peripheral primitive neuroectodermal tumor. About 85% harbor the t(11;22) (q24;q12) fusion by fluorescence in situ hybridization producing a chimeric protein central to pathogenesis. EES is rare, highly aggressive, and prone to recurrence, typically affecting adolescents and young adults and arising in the trunk or lower limbs; primary breast origin is exceptionally uncommon and carries a poor prognosis relative to other breast malignancies and versus other extra-skeletal ES sites. We report the case of a 37-year-old woman with a rapidly enlarging breast mass. Imaging suggested a cystlike lesion; a core biopsy was non-diagnostic. Wide excision established ES. She received neoadjuvant chemotherapy with complete response, followed by mastectomy. This case and literature review underscore the rarity of primary breast ES and the value of neoadjuvant chemotherapy in management.
2026-02-04 | Characterization of stiffness as a biomarker in osteoarthritis and in bone- and soft tissue cancers
Mechanobiology encompasses all of the mechanical processes that influence the cell and its environment. Thereby, the major actors are the cell´s structural components (i.e. cell membrane, cytoskeleton), the components of the extracellular matrix (ECM), and the interface between both (i.e. mechanosensors, adhesion molecules). It is well established that biomechanics plays a critical role in the homeostasis of living tissue, but the concrete mechanisms by which mechanical cues are assimilated and regulate the balance between health and disease are not yet fully understood. In recent decades, atomic force microscopy (AFM) has emerged as the gold standard to measure the foremost mechanical marker of a tissue/cell, namely the stiffness (measured as the Young´s modulus). This parameter provides important information about the state of a living entity, and can be used to investigate a diseased/degenerative condition. In the present work, AFM was employed to characterize the biomechanical alterations occurring during two major disorders from the orthopedic field: osteoarthritis (OA) and bone/soft-tissue cancers. OA is defined as a degenerative joint condition, characterized by articular cartilage destruction. With progression of the disease the chondrocyte organization pattern is evolving, from single string (SS) in healthy cartilage to double string (DS), small cluster (SC), big cluster (BC) and finally diffuse pattern in the most advanced arthritic state. Cartilage discs of 1mm thickness and 4mm diameter were generated from condyles of patient undergoing total knee arthroplasty and were sorted according to the aforementioned cellular patterns. Subsequently the stiffness of the discs was measured with AFM. A stepwise stiffness decrease was observed with an increasing degeneration level, except for the group of the diffuse pattern, which displayed a large data spread with a relatively high stiffness on average. The discs used for those experiments have the advantage of being of appreciable thickness, they exhibit the native cartilage surface at their upmost side and the cells within the tissue are kept alive. They hence represent a suitable model to further investigate articular cartilage degenerative processes in situ. Bone and soft-tissue sarcomas represent a group of diverse cancer entities from mesenchymal origin, with overall poor prognosis. The stiffness of malignant cells of five different bone and soft-tissue sarcoma cell lines were investigated using AFM and were compared to their respective healthy control cells. Osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma cells were significantly less stiff than osteoblasts, 66 Mesenchymal stem cells (MSCs), fibroblasts and skeletal muscle cells (SKMCs) respectively, reflecting a typical feature observed in most of the neoplastic transformation. However, chondrosarcoma cells appeared to be stiffer than chondrocytes and the other malignant cell lines. Further cytoskeleton examination using fluorescence microscopy, ELISA and qPCR revealed that if most of the malignant cells displayed a disorganized internal scaffold and a decreased F-actin content, chondrosarcoma maintained a cytoskeletal structure relatively close to the one of the healthy cells, with the microtubule being the most affected components (increase in the β-tubulin gene expression and protein content). These results define the biomechanical fingerprints of the investigated cancer cell lines and expose the related molecular mechanisms. Overall, the work presented in this thesis contributes to the effort of mechanical characterization of the biological systems respectively addressed in the disclosed studies. Understanding the processes underlying the biomechanical properties of cells and tissue is of upmost importance for the development of novel diagnostic and therapy approaches.
2025-10-14 | KDM6 Demethylases Contribute to EWSR1::FLI1-Driven Oncogenic Reprogramming in Ewing Sarcoma.
Ewing sarcoma is a highly aggressive tumor arising in bones and soft tissues, driven by the fusion oncoprotein EWSR1::FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neoenhancers in a permissive cellular context. Inhibition of the oncogene remains challenging, and current efforts seek to exploit emergent epigenetic treatments targeting EWSR1::FLI1 cofactors. In Ewing sarcoma, neoenhancers are characterized by strong enrichment of the active H3K27ac mark and a concomitant lack of the repressive H3K27me3 mark. These regions are typically decorated with high levels of H3K27me3 prior to EWSR1::FLI1 activation. In this study, upon expression of EWSR1::FLI1 in human pediatric mesenchymal stem cells, considered the putative cell of origin of Ewing sarcoma, we unraveled the genome-wide redistribution of H3K27me3. Stemming from these results, we elucidated the contribution of the H3K27me3 demethylases KDM6A/UTX and KDM6B/JMJD3 in the transcriptional activity of EWSR1::FLI1-induced enhancers. KDM6A had a demethylase-independent role in recruiting BRG1 at EWSR1::FLI1-primed enhancers containing single GGAA motifs, which was critical for Ewing sarcoma tumor growth. Conversely, KDM6B demethylated H3K27me3 at specific EWSR1::FLI1-active enhancers, colocalizing with BRG1 at GGAA repeats. Loss of KDM6B impaired the growth of Ewing sarcoma tumor xenografts. These results highlight KDM6 demethylases as EWSR1::FLI1 functional partners with potential as targets for treating Ewing sarcoma. KDM6A and KDM6B mediate critical mechanisms behind EWSR1::FLI1 transcriptional activation program involving demethylase-independent and dependent functions, respectively, supporting the development of therapeutic strategies targeting these demethylases in Ewing sarcoma.
2025-08-22 | Rare case of Infiltrative multifocal Ewing sarcoma presenting as neck mass.
Ewing sarcoma is a rare, highly aggressive small round cell tumor that primarily affects the bones of adolescents and young adults, with extra skeletal involvement being particularly uncommon. We present the case of an 18-year-old male with a progressively enlarging, painful swelling in the right posterior neck, ultimately diagnosed as Extra skeletal Ewing sarcoma involving the occipital bone and C1 vertebra. Imaging revealed extensive intracranial, intraspinal, and paravertebral extension with multiple skeletal metastases. Histopathological and immunohistochemical analysis confirmed the diagnosis, showing NKX 2.2 positivity. The patient was initiated on systemic chemotherapy using the VDC/IE regimen, leading to significant clinical and radiological improvement. This case underscores the importance of considering Ewing sarcoma in atypical paraspinal and cranial presentations and highlights the critical role of early multimodal imaging and chemotherapy in managing aggressive disease.
2025-05-26 | Transforming bone cancer treatment: a comprehensive review of green-synthesized metal nanoparticles.
Osteosarcoma (OS), chondrosarcoma (CHS), and Ewing sarcoma (EWS) are the main types of bone cancer (BC). OS is the most common BC in this group. It is most common in children and older people, especially in their long bones. Treatments for bone sarcomas and tumors have slowly improved, so researchers began looking into additional and alternative approaches to standard therapies. Therefore, the ability to precisely manipulate metallic nanoparticles (MNPs)' form, size, charge, and surface modification makes them very useful in treating bone cancer. However, due to the biocompatibility and possible toxicity of MNPs, MNP has limits for clinical use in treating BC. Therefore, the green synthesis of MNPs is achieved by bio-reducing metallic ions, which results in the creation of NPs, using living entities or their extracts. Green MNPs derived from natural sources provide a secure and environmentally responsible solution. Benefits of green MNPs include tailored medicine delivery and biocompatibility. Green MNPs reduce damage to healthy cells while improving the targeting of bone cancer cells. In this study, we reviewed how different MNPs synthesized using green methods can help treat various types of BC. This work reviewed the usual way of making MNPs for treating BC, the problems with this standard way of making MNPs, and the benefits and possible future uses of green synthetic MNPs for treating BC.
proteins
2026-01-03 | RUNX2 Represses the EWS-FLI1-mediated Transcription in Ewing's Sarcoma Cells.
Ewing's sarcoma is an aggressive pediatric malignancy driven by specific chromosomal translocations, predominantly leading to the oncogenic fusion protein EWS-FLI1. Runt-related transcription factors 1 and 2 (RUNX1 and RUNX2), which are key transcription factors involved in osteoblastic differentiation and skeletal morphogenesis, are not expressed in Ewing's sarcoma. Our study aimed to elucidate the relationship between the RUNX genes and EWS-FLI1. We used Ewing's sarcoma cell lines (A673 and NCR-EW2). EWS-FLI1 knockdown was achieved using shRNA, while inducible expression of RUNX1, RUNX2, EWS-FLI1, or EWS-ERG was performed using a Tet-on system. Gene and protein expression levels were quantitatively assessed by qPCR and Western blot analysis, respectively. Cell growth was evaluated using spheroid formation and cell viability assays. Truncated RUNX1 or RUNX2 constructs were employed to identify functional domains, with their intracellular localization confirmed by immunostaining. We observed low expression of RUNX1 and RUNX2 in Ewing's sarcoma cells. Notably, EWS-FLI1 knockdown increased RUNX2 gene expression. Conversely, inducible expressions of either RUNX1 or RUNX2 suppressed the expression of EWS-FLI1 target genes and inhibited cell proliferation and spheroid formation. Additionally, the RUNT domain of RUNX1 and RUNX2 was not essential for their inhibitory effect on EWS-FLI1 target gene expression. Importantly, both EWS-FLI1 and EWS-ERG down-regulated RUNX2 gene expression in hTert-RPE1 cells. EWS-FLI1 suppresses RUNX2 gene expression in Ewing's sarcoma cells, and re-expressing RUNX2 inhibits cell growth. These findings suggest that RUNX2 has a negative impact on the oncogenic process in Ewing's sarcoma.
2013-09-01 | Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL
Ewing's sarcoma (ES) associated with high osyeolytic lesions typically arises in the bones of children and adolescents. The development of multi-disciplinary therapy has increased current long-term survival rates to greater than 50% but only 20% for high risk group patients (relapse, metastases, etc.). Among new therapeutic approaches, osteoprotegerin (OPG), an anti-bone resorption molecule may represent a promising candidate to inhibit RANKL-mediated osteolytic component of ES and consequently to limit the tumor development. Xenogenic orthotopic models of Ewing's sarcoma were induced by intra-osseous injection of human TC-71 ES cells. OPG was administered in vivo by non-viral gene transfer using an amphiphilic non ionic block copolymer. ES bearing mice were assigned to controls (no treatment, synthetic vector alone or F68/empty pcDNA3.1 plasmid) and hOPG treated groups. A substantial but not significant inhibition of tumor development was observed in the hOPG group as compared to control groups. Marked bone lesions were revealed by micro-computed tomography analyses in control groups whereas a normal bone micro-architecture was preserved in the hOPG treated group. RANKL over-expressed in ES animal model was expressed by tumor cells rather than by host cells. However, TRAIL present in the tumor microenvironment may interfere with OPG effect on tumor development and bone remodeling via RANKL inhibition. In conclusion, the use of a xenogenic model of Ewing's sarcoma allowed discriminating between the tumor and host cells responsible for the elevation of RANKL production observed in this tumor and demonstrated the relevance of blocking RANKL by OPG as a promising therapy in ES.
2011-05-01 | Trail sensitivity in Ewing's sarcoma patients is modulated by the expression of death receptor 4 and its short isoform despite predominant dr5 level
Activation of cell surface death receptors by their cognate ligands triggers apoptosis. Several human death receptors (Fas, TNF-R1, TRAMP, DR4, DR5, DR6, EDA-R and NGF-R) have been identified. The most promising cytokine for anticancer therapy is TRAIL/APO-2L, which induces apoptosis in cancer cells by binding to death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. The cytotoxic activity of TRAIL is relatively selective to cancer cells compared to normal cells. Signaling by TRAIL and its receptors is tightly regulated process essential for key physiological functions in a variety of organs, as well as the maintenance of immune homeostasis. Despite early promising results, recent studies have identified several TRAIL-resistant cancer cells of various origins. Based on molecular analysis of death-receptor signaling pathways several new approaches have been developed to increase the efficacy of TRAIL. Resistance of cancer cells to TRAIL appears to occur through the modulation of various molecular targets. They may include differential expression of death receptors, constitutively active Akt and NFκB, overexpression of cFLIP and IAPs, mutations in Bax and Bak genes, and defects in the release of mitochondrial proteins in resistant cells. Conventional chemotherapeutic and chemopreventive drugs, and irradiation can sensitize TRAIL-resistant cells to undergo apoptosis. Thus, these agents enhance the therapeutic potential of TRAIL in TRAIL-sensitive cells and sensitize TRAIL-resistant cells. TRAIL and TRAIL-receptor antibodies may prove to be useful for cancer therapy, either alone or in association with conventional approaches such as chemotherapy or radiation therapy. This review discusses intracellular mechanisms of TRAIL resistance and various approaches that can be taken to sensitize TRAIL-resistant cancer cells.
2010-12-22 | Osteoprotegerin inhibitits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL produced by tumor cells
reduces it. Luciferase assays and co-immunoprecipitation revealed that Twist forms a transcription complex with NFkB through its RBD domain to activate IL-8 promoter. In addition, the DNA binding ability is also required for this activation. Furthermore, increases in IL-8 production elevated the invasive potential of Twist over-expressing cells through activation of metalloproteinase. Using IL-8 neutralizing antibodies and blockage of IL-8 receptors (CXCR1/2) activation resulted in decreased MMP9 production and activation, and subsequently decrease in invasive ability of Twist over-expression breast cancer cells. Collectively, our results demonstrate that Twist overexpression in breast epithelial cells promotes their transformation and enhances their invasive capabilities through IL-8 production.
2010-04-07 | Preclinical Evidence that Use of TRAIL in Ewing's Sarcoma and Osteosarcoma Therapy Inhibits Tumor Growth, Prevents Osteolysis, and Increases Animal Survival
Abstract Purpose: Osteosarcoma and Ewing's sarcoma are high-grade neoplasms typically arising in the bones of children and adolescents. Despite improvement in therapy, the five-year survival rate is only 20% for patients not responding to treatment or presenting with metastases. Among new therapeutic strategies, the efficacy of tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily with strong antitumoral activity and minimal toxicity to most normal cells and tissues, was investigated by complementary approaches both in vitro and in preclinical models. Experimental design: The sensitivity of osteosarcoma and Ewing’s sarcoma cell lines to TRAIL was investigated in vitro by determining TRAIL receptor expression together with TRAIL effects on cell viability and apoptosis. Complementary preclinical studies were carried out in respective tumor models by inoculation of osteosarcoma or Ewing’s sarcoma tumor cells in paraosseous location. In addition, a model of lung nodule dissemination was developed by i.v. injection of osteosarcoma cells. Results: In vitro, both osteosarcoma and Ewing’s sarcoma cells that express the TRAIL death receptors were highly sensitive to TRAIL-induced caspase-8–mediated apoptosis. TRAIL administered in vivo by nonviral gene therapy inhibited primary bone tumor incidence and growth by 87% and prevented tumor-induced osteolysis, leading to a significant 2-fold increase in animal survival 40 days after tumor induction. Furthermore, TRAIL inhibited tumor nodule dissemination in lungs and increased survival in an osteosarcoma model. Conclusion: These findings suggest that TRAIL is a promising candidate for the development of new therapeutic strategies in the most frequent malignant primary bone tumors. Clin Cancer Res; 16(8); 2363–34. ©2010 AACR.
antibodies
2026-01-10 | Age-Related Clinicopathologic Patterns in Ewing Sarcoma (FET::ETS Family): A Comparative Analysis of Pediatric and Adult Patients.
Background: Ewing sarcoma (ES) is a rare, aggressive small round cell sarcoma (SRCS) that peaks in adolescence. Given its rarity, atypical age or site presentations increase the risk of misclassification. This study examines age-related clinicopathological patterns in molecularly confirmed canonical ES (FET::ETS-fused). Methods: Between 2016 and 2025, 90 tumors diagnosed as ES or Ewing-like SRCSs underwent targeted RNA sequencing and/or EWSR1 break-apart fluorescence in situ hybridization. Patients were stratified into three age groups: 0-18, 19-39, and ≥40 years. Clinical, anatomical, pathological, molecular, and treatment/outcome variables were compared across strata. Results: Canonical ES accounted for 84% (76/90) of SRCSs, dominated by EWSR1::FLI1 (89%). ES comprised 91% of SRCSs in children but declined to 75% in older adults. Tumors arose mainly in bone (63%), with a significant age association (p = 0.016): children and young adults were primarily skeletal (73% and 62%), whereas older adults were predominantly extraskeletal (78%). Renal ES clustered in adults ≥40 years (p = 0.003). Classic histology predominated; atypical patterns were more common in extraskeletal tumors but lacked age specificity. Ewing-like SRCSs (n = 14), with heterogeneous or absent fusions, displayed a broader age distribution-including infants and older adults-and a marked extraskeletal predominance (86%, p = 0.001). Metastatic presentation strongly predicted inferior survival (p = 0.025). Treatment was multimodal, with neoadjuvant chemotherapy more frequent in children (90%, p = 0.029). Conclusions: Age significantly influences anatomic presentation and certain treatment choices in ES, whereas histology and survival remain broadly similar across groups. Age-linked extraskeletal trends reinforce the importance of routine molecular testing, particularly in underreported Middle Eastern populations.
2026-01-01 | Integrated Immunotherapy Target Atlas for Ewing Sarcoma
The purpose of this study was to convert ESS32 from a fusion-associated RNA signature into a compartment-aware immunotherapy target atlas. We integrated GEO transcriptomic cohorts with HPA-derived normal-tissue, protein, subcellular, and secretome information, together with published proteomic and surfaceome evidence, to assign each candidate to a practical therapeutic target class. Our goal was to generate a ranked, biologically interpretable candidate list with explicit validation requirements. In doing so, we asked four linked questions: which ESS32 and comparator genes are most enriched in Ewing tumor relative to skeletal muscle; which of these signals recur across supportive tumor, model, perturbation, or cross-sarcoma contexts; how normal-tissue and protein-level evidence reorder RNA-ranked candidates; and which candidates are most compatible with TCR/vaccine, antibody/ADC/CAR, radioligand, biomarker, or validation-first development paths.
2025-08-26 | Partial surgical excision of ewing sarcoma in the lower mandible of an 11-year-old boy with dental malocclusion.
Ewing sarcoma (ES) is an uncommon and aggressive tumor that primarily affects children and adolescents, peaking in incidence between the ages of 10 and 20. Although it most frequently occurs in long bones and the pelvis, its presence in the lower mandible is extremely rare, creating notable challenges in both diagnosis and treatment. This report details an 11-year-old boy from a low-income background who was diagnosed with Ewing sarcoma localized to the lower mandible. Initially, he presented with ongoing pain and swelling, which were mistakenly attributed to dental problems, resulting in a delayed diagnosis. Imaging studies identified a permeative bone lesion, which was confirmed through biopsy to be Ewing sarcoma with the EWSR1-FLI1 fusion gene. The patient underwent partial surgical excision followed by a chemotherapy regimen. Unfortunately, he developed neutropenia and septic shock during treatment, leading to his eventual death. This case highlights the diverse clinical presentations of Ewing sarcoma, stressing the necessity for heightened awareness of malignant conditions in pediatric patients. It also discusses the socioeconomic factors that can delay diagnosis, underscoring the importance of raising awareness in underserved areas. A multidisciplinary treatment approach is essential, along with careful monitoring for complications. This case exemplifies the challenges in diagnosing and managing Ewing sarcoma in atypical sites such as the mandible. It emphasizes the need for early symptom recognition, addressing socioeconomic disparities and implementing comprehensive care strategies to enhance patient outcomes in pediatric oncology.
2025-05-26 | Ewing Sarcoma Family of Tumors (ESFTs) of Renal Origin Presenting With Bone Metastases: A Case Report.
We report a unique case of a female patient in her fifth decade of life who presented with groin pain and was found to have a right kidney mass measuring approximately 8 cm, in addition to multiple bone metastases. Both the nephrectomy specimen and the bone biopsy were found to belong to the Ewing sarcoma family of tumors (ESFTs). This was confirmed by immunohistochemical studies and fluorescence in situ hybridization (FISH) showing EWSR1 gene rearrangement. Molecular analysis with next-generation sequencing (NGS) showed a type II EWSR1:FLI1 gene fusion. The patient's disease progressed rapidly, and she passed away approximately three months after admission. Although extremely rare in the kidney, ESFT should be considered in patients who present with clinically aggressive kidney tumors.
2025-03-19 | Prolonged atraumatic back pain in an adolescent female: Emergency department presentation of Ewing's Sarcoma.
Back pain and syncope are two common complaints encountered in the emergency department. However, prolonged atraumatic back pain in a pediatric patient should always be considered a "red flag" symptom. We describe a case of a 14-year-old female who presented to the emergency department with syncope and hypotension due to low back pain who was ultimately diagnosed with Primary Ewing's Sarcoma (ES) of the lumbar spine with extensive pulmonary metastasis. The diagnosis was expedited by the use of a bedside RUSH exam that identified an otherwise asymptomatic, unilateral pleural effusion. ES is the second most common primary bone malignancy in adolescents and young adults and unfortunately has a delayed diagnosis due to vague and non-specific symptoms. Survival rates of metastatic ES are still quite poor despite advances in therapies and treatments. This case emphasizes the importance of obtaining a focused history and physical exam, and how targeted point-of-care ultrasonography can aid in the diagnosis of rare and life-threatening conditions.
other
2025-04-21 | Abstract 106: Growth-associated protein 43 (GAP-43): the link to Ewing sarcoma bone metastasis
Abstract Ewing Sarcoma (ES) is an aggressive pediatric tumor that arises in bone or soft tissues. ES bone metastases do not respond well to routine therapies and their frequency markedly increases upon disease recurrence, which results in a lower survival rate in patients with osseous metastases as compared to those with pulmonary dissemination. Our previous studies have determined that ES bone metastasis is initiated by hypoxia in the primary tumor site, which leads to the formation of polyploid tumor cells, the progeny of which, named HYP-4n cells, exhibit high levels of chromosomal instability. These cells metastasize almost exclusively to bone and are less sensitive to cytostatic agents. In this study, we demonstrate that HYP-4n cells exhibit an upregulation in several neuronal proteins, specifically growth-associated protein 43 (GAP-43), a membrane protein promoting axon growth in neurons and formation of microtubes connecting glioblastoma cells into invasive and therapy-resistant cellular network. Similar phenotype characterized by the presence of microtube-like cell-cell connections was also observed in ES HYP-4n cells. GAP-43 immunostaining in HYP-4n cells revealed a punctuated pattern along the protrusions that is similar to its localization in neurons. Western Blot analysis performed on HYP-4n cells revealed a membranous localization of GAP-43, which was not detectable in their normoxic diploid counterparts. The functional role of the GAP-43-positive protrusions in connecting HYP-4n cells was confirmed by the gap-junction permeable dye transfer between the cells and ion transfer detected by a patch clamp assay. DAPI staining also displayed nuclear fragments within the protrusions, suggesting the transfer of genetic material. The suppression of GAP-43 expression via siRNA was further shown to inhibit HYP-4n cell migration measured via transwell assay. In immunostained ES xenografts, GAP-43 expression was shown in HYP-4n primary and osseous metastatic tumors, with the highest membranous expression in the ES cells on the invading edge of the tumors. A similar pattern of expression of GAP-43 was noted in the human samples of ES bone metastases. This study indicates that GAP-43 is active in the membrane in HYP-4n cells and drives the formation of microtube networks promoting cell invasion. Further studies are required to prove directly the role of GAP-43 in ES bone metastasis and chemoresistance. Citation Format: Tyler Biermann, Nicholas Cohen, Yasmine Wazni, Stefano Vicini, Jason Tilan, Joanna Kitlinska. Growth-associated protein 43 (GAP-43): the link to Ewing sarcoma bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 106.
2023-09-23 | Oncomeric Profiles of microRNAs as New Therapeutic Targets for Treatment of Ewing’s Sarcoma: A Composite Review
Ewing's sarcoma is a rare type of cancer that forms in bones and soft tissues in the body, affecting mostly children and young adults. Current treatments for ES are limited to chemotherapy and/or radiation, followed by surgery. Recently, microRNAs have shown favourable results as latent diagnostic and prognostic biomarkers in various cancers. Furthermore, microRNAs have shown to be a good therapeutic agent due to their involvement in the dysregulation of various molecular pathways linked to tumour progression, invasion, angiogenesis, and metastasis. In this review, comprehensive data mining was employed to explore various microRNAs that might have therapeutic potential as target molecules in the treatment of ES.
2023-02-27 | Integrative analyses of bulk microarray data to discover genes, pathways, and immune infiltration characteristics associated with targeting of Ewing sarcoma
Abstract Purpose To explore transcriptome and immunological features of patients with Ewing sarcoma (ES) using all publicly available microarray data. Methods Data of 479 ES tissues were integrated and normalized. Gene expression, immune infiltration, and cancer-specific pathways were analyzed. Genes of interest were knocked down, followed by cell proliferation and colony formation assays. Results Consistent with the previous reports of differential expressed genes (DEGs) in ES, our analysis identified CCND1 , HMCN1 , and NKX2-2 were among the most highly expressed, while TWNC1 , MYBPC1 , and CKM were among the lowest expressed genes. GO, KEGG, and GSEA enrichment analysis identified that the DEGs related to bone and muscle functioning, those that contributed to crucial cellular, and metabolism pathways such as actin binding, apoptosis, TCA cycle, and cell cycle were also significantly enriched. Immune infiltration analysis discovered that many T cell subsets including CD4T, CD8 T, and Gamma delta T cells were highly infiltrated, while monocytes and B cells were less infiltrated in tumors. A total of 138 genes were both significantly up-regulated in tumors and associated with decreased survival, while 38 significantly down-regulated genes were associated with increased survival, many of which were previously reported as oncogenes and tumor suppressors in ES and other cancers. Silencing of four newly identified top ranked up-regulated genes with decreased survivals in ES inhibited proliferation and colony formation of ES cells. Conclusion This study may provide a clear representative transcriptome profile of ES, providing diagnostic biomarkers, pathways, and immune infiltrative characteristics targets for ES.
2019-09-27 | Tumour-Derived Extracellular Vesicles (EVs): A Dangerous “Message in A Bottle” for Bone
Several studies have shown the importance of Extracellular Vesicles (EVs) in the intercellular communication between tumour and resident cells. Through EVs, tumour cells can trigger cell-signalling molecules and shuttle exogenous information to target cells, thus promoting spread of the disease. In fact, many processes are fuelled by EVs, such as tumour invasion and dormancy, drug-resistance, immune-surveillance escape, extravasation, extracellular matrix remodelling and metastasis. A key element is certainly the molecular profile of the shed cargo. Understanding the biochemical basis of EVs would help to predict the ability and propensity of cancer cells to metastasize a specific tissue, with the aim to target the release of EVs and to manipulate their content as a possible therapeutic approach. Moreover, EV profiling could help monitor the progression of cancer, providing a useful tool for more effective therapy. This review will focus on all the EV-mediated mentioned mechanisms in the context of both primary bone cancers and bone metastases.
2018-02-13 | miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors.
Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73β, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73β. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73β axis in the context of these malignancies.
cell therapies
2026-04-03 | Abstract 5426: Anatomic origins of primary skeletal tumors effect metastatic and prognostic behaviors.
Abstract Introduction: This study investigates the histology of nonmetastatic primary skeletal tumors related to their anatomic origin and its influence on 5-year survival outcomes. Methodology: Deidentified patient data were obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Inclusion criteria included: (1) diagnosis of a primary bone cancer with anatomical location of origin, classified using ICD-O-3 anatomic site codes; (2) documented absence of metastasis to the brain, lung, liver, or bone; (3) cause-specific death and survival duration; and (4) available histology codes. Patients were stratified by primary tumor location and histologic sub-type. Kaplan-Meier survival curves were used to estimate survival, and group differences were assessed with pairwise log-rank tests. A p-value <0.05 was considered statistically significant. Results: The top five most common nonmetastatic skeletal tumors by histology are Chondrosarcoma, Osteosarcoma, Chondroma, Ewing Sarcoma, and Diffuse Large B-Cell Lymphoma (DLBCL). The tumor location distribution and 5-year survival for each histological subclass are outlined in Table 1. Conclusion: The differences in anatomic origin of primary bone tumors when controlled for histologic category influences patient mortality. There are distinct differences in overall survival compared among origin sites, signifying a location-based influence on disease severity and survival. The knowledge of anatomic origin differences of survival of various histologic categories of bone cancer can improve clinical decision making and create more accurate, locational based planning when looking at prognosis and disease progression. Citation Format: Matthew Duazo, Aayush Bhatawadekar, Dillon Pekoff, Maria Plummer, Brian Beatty, . Anatomic origins of primary skeletal tumors effect metastatic and prognostic behaviors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5426.
2025-12-26 | Aggressive Ewing Sarcoma of the Mandible in a Child: A Case Report
Ewing sarcoma is a highly aggressive malignant bone tumor which most commonly arises in the long bones and pelvis of adolescents and young adults. Craniofacial involvement, particularly of the mandible, is extremely rare and may mimic odontogenic or inflammatory lesions, leading to diagnostic delay. We report the case of a 14-year-old girl with histologically confirmed Ewing sarcoma of the left mandible. Clinical and initial radiological findings suggested an aggressive mandibular lesion with locoregional extension. For comprehensive baseline evaluation, an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was performed. It demonstrated intense metabolic activity of the mandibular mass, consistent with high tumor aggressiveness, while excluding cervical, thoracic, abdominal, and skeletal metastases. This case underlines the crucial role of 18F-FDG PET/CT not only in the initial staging of Ewing sarcoma but also in the differential diagnosis of atypical mandibular swellings in children and adolescents. By combining functional and anatomical data, PET/CT improves diagnostic confidence, guides therapeutic planning, and contributes to prognostic assessment in such uncommon presentations.
2025-11-14 | [Reconstruction of primary malignant bone tumors in children: Do we really need to change our methods?].
Primary bone tumors in children are almost exclusively represented by osteosarcomas and Ewing sarcomas. They mainly affect the limbs, particularly the lower limbs. It is estimated that there are approximately 250 new cases per year. While the initial goal is survival, the question of reconstruction quickly follows. The aim of reconstruction is to avoid amputation, ensure functional outcomes, and, if possible, support ongoing growth in these children. For a long time, free fibula transfer was the first choice, as it allowed for the use of a vascularized bone whose shape was well-suited for limb reconstruction. Later, the induced membrane technique, also known as the Masquelet technique, was introduced. New radiotherapy protocols led to a preference for this latter technique. One of the arguments was that the risk of nonunion or delayed union would be too high with fibula grafts. So much so that, in our experience, no free fibula transfers were performed between 2015 and 2020. However, the analysis of the data from our series shows quite the opposite and does not support the superiority of the Masquelet technique (quite the contrary). Moreover, the fibula remains irreplaceable in certain indications (joint reconstruction, growth plate reconstruction, bi- or trifoliate graft reconstruction, etc.). Therefore, based on the analysis of our experience, the free fibula graft does not appear to be inferior in the specific context of bone reconstruction in children following malignant tumor resection.
2025-11-11 | Evaluation of the results of combined free vascularized fibular graft and pasteurized tumor segment for the reconstruction of intercalary femoral defects following tumor resection.
the reconstruction of intercalary femoral defects after tumour resection is challenging. We have evaluated the clinical, functional, and oncological results of using free vascularized fibular graft combined with preserved pasteurized tumour segment. this study was retrospective in nature and included 12 patients [eight males and four females]. The mean age was 21.3 years ± 11.3. The diagnoses of the patients were osteosarcoma (Five cases) and Ewing's sarcoma (seven cases). The resection was wide local excision, and the defect was reconstructed using combined free vascularized fibular graft and pasteurized tumour segment. the mean time to union was 7.1 ± 1.9 months while the mean time to full weight bearing was 12 ± 1.8 months. The mean size of skeletal defect was 17.7 cm ± 1.92. The mean duration of surgery was 12.1 h ± 1.88. Nonunion occurred in four cases, stress fractures occurred in two cases and metal failure occurred in one case. the combined technique of using free vascularized fibular graft and pasteurized tumour segment for intercalary femoral defects following tumour resection is a valuable technique with accepted complications and good results.
2025-10-01 | Comparison of Biological Reconstruction After Resection of Proximal Humerus Bone Sarcomas in Pediatric Patients
Background: The aim of this study was to investigate the clinical outcomes and complications of vascularized fibular epiphyseal transfer (VFET) and clavicle pro humero (CPH) for proximal humeral reconstruction after primary sarcoma resection in skeletally immature patients. Patients and Methods: This retrospective case-control study included 29 skeletally immature patients (18 male patients, 11 female patients) with primary bone sarcomas who were treated between January 2009 and June 2023 at Beijing Jishuitan Hospital. The average age was 9.4 ± 2.8 years (range, 5-14), and the pathological type included osteosarcoma (25) and Ewing sarcoma (4). We compared the graft survival, function, and complication rate between the VFET group and the CPH group. Results: The 2-year and 5-year overall survival rates for the VFET group and CPH group were 94%, 75%, 86%, and 55%, respectively. The 2-year and 5-year revision-free survival for the VFET group and CPH group were 77%, 61%, 75%, and 37%, respectively. At the final follow-up, the mean MSTS-93 score in the VFET group was 82% (67%-97%), while the mean MSTS-93 score in the CPH group was 79% (73%-96%, p > 0.05). The incidence of mechanical complications was significantly higher in the CPH group (88%, 7/8) than that in the VFET group (52%, 11/21) (p = 0.036). The mean difference in upper limb length in the VFET group was 5.0 ± 2.9 cm and 10.2 ± 4.2 cm in the CPH group (p = 0.003). Conclusions: We suggest that vascularized fibular epiphyseal transfer may be considered as a promising biological reconstruction option for pediatric patients with proximal humeral osteosarcoma who have a longer life expectancy. For institutions lacking the necessary microsurgical techniques, clavicle pro humero reconstruction remains a relatively simple and feasible alternative reconstruction option. Level of Evidence: Level III Case-control study. See Instructions for Authors for a complete description of levels of evidence.
small molecules
2026-03-02 | Primary breast Ewing sarcoma in a young adult: diagnostic challenges and neoadjuvant chemotherapy success<b></b>
Extra-skeletal Ewing Sarcoma (EES) is a malignant soft-tissue tumor morphologically indistinguishable from osseous Ewing Sarcoma (ES). The Ewing family includes ES, EES, Askin tumor, and peripheral primitive neuroectodermal tumor. About 85% harbor the t(11;22) (q24;q12) fusion by fluorescence in situ hybridization producing a chimeric protein central to pathogenesis. EES is rare, highly aggressive, and prone to recurrence, typically affecting adolescents and young adults and arising in the trunk or lower limbs; primary breast origin is exceptionally uncommon and carries a poor prognosis relative to other breast malignancies and versus other extra-skeletal ES sites. We report the case of a 37-year-old woman with a rapidly enlarging breast mass. Imaging suggested a cystlike lesion; a core biopsy was non-diagnostic. Wide excision established ES. She received neoadjuvant chemotherapy with complete response, followed by mastectomy. This case and literature review underscore the rarity of primary breast ES and the value of neoadjuvant chemotherapy in management.
2026-02-04 | Characterization of stiffness as a biomarker in osteoarthritis and in bone- and soft tissue cancers
Mechanobiology encompasses all of the mechanical processes that influence the cell and its environment. Thereby, the major actors are the cell´s structural components (i.e. cell membrane, cytoskeleton), the components of the extracellular matrix (ECM), and the interface between both (i.e. mechanosensors, adhesion molecules). It is well established that biomechanics plays a critical role in the homeostasis of living tissue, but the concrete mechanisms by which mechanical cues are assimilated and regulate the balance between health and disease are not yet fully understood. In recent decades, atomic force microscopy (AFM) has emerged as the gold standard to measure the foremost mechanical marker of a tissue/cell, namely the stiffness (measured as the Young´s modulus). This parameter provides important information about the state of a living entity, and can be used to investigate a diseased/degenerative condition. In the present work, AFM was employed to characterize the biomechanical alterations occurring during two major disorders from the orthopedic field: osteoarthritis (OA) and bone/soft-tissue cancers. OA is defined as a degenerative joint condition, characterized by articular cartilage destruction. With progression of the disease the chondrocyte organization pattern is evolving, from single string (SS) in healthy cartilage to double string (DS), small cluster (SC), big cluster (BC) and finally diffuse pattern in the most advanced arthritic state. Cartilage discs of 1mm thickness and 4mm diameter were generated from condyles of patient undergoing total knee arthroplasty and were sorted according to the aforementioned cellular patterns. Subsequently the stiffness of the discs was measured with AFM. A stepwise stiffness decrease was observed with an increasing degeneration level, except for the group of the diffuse pattern, which displayed a large data spread with a relatively high stiffness on average. The discs used for those experiments have the advantage of being of appreciable thickness, they exhibit the native cartilage surface at their upmost side and the cells within the tissue are kept alive. They hence represent a suitable model to further investigate articular cartilage degenerative processes in situ. Bone and soft-tissue sarcomas represent a group of diverse cancer entities from mesenchymal origin, with overall poor prognosis. The stiffness of malignant cells of five different bone and soft-tissue sarcoma cell lines were investigated using AFM and were compared to their respective healthy control cells. Osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma cells were significantly less stiff than osteoblasts, 66 Mesenchymal stem cells (MSCs), fibroblasts and skeletal muscle cells (SKMCs) respectively, reflecting a typical feature observed in most of the neoplastic transformation. However, chondrosarcoma cells appeared to be stiffer than chondrocytes and the other malignant cell lines. Further cytoskeleton examination using fluorescence microscopy, ELISA and qPCR revealed that if most of the malignant cells displayed a disorganized internal scaffold and a decreased F-actin content, chondrosarcoma maintained a cytoskeletal structure relatively close to the one of the healthy cells, with the microtubule being the most affected components (increase in the β-tubulin gene expression and protein content). These results define the biomechanical fingerprints of the investigated cancer cell lines and expose the related molecular mechanisms. Overall, the work presented in this thesis contributes to the effort of mechanical characterization of the biological systems respectively addressed in the disclosed studies. Understanding the processes underlying the biomechanical properties of cells and tissue is of upmost importance for the development of novel diagnostic and therapy approaches.
2025-10-14 | KDM6 Demethylases Contribute to EWSR1::FLI1-Driven Oncogenic Reprogramming in Ewing Sarcoma.
Ewing sarcoma is a highly aggressive tumor arising in bones and soft tissues, driven by the fusion oncoprotein EWSR1::FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neoenhancers in a permissive cellular context. Inhibition of the oncogene remains challenging, and current efforts seek to exploit emergent epigenetic treatments targeting EWSR1::FLI1 cofactors. In Ewing sarcoma, neoenhancers are characterized by strong enrichment of the active H3K27ac mark and a concomitant lack of the repressive H3K27me3 mark. These regions are typically decorated with high levels of H3K27me3 prior to EWSR1::FLI1 activation. In this study, upon expression of EWSR1::FLI1 in human pediatric mesenchymal stem cells, considered the putative cell of origin of Ewing sarcoma, we unraveled the genome-wide redistribution of H3K27me3. Stemming from these results, we elucidated the contribution of the H3K27me3 demethylases KDM6A/UTX and KDM6B/JMJD3 in the transcriptional activity of EWSR1::FLI1-induced enhancers. KDM6A had a demethylase-independent role in recruiting BRG1 at EWSR1::FLI1-primed enhancers containing single GGAA motifs, which was critical for Ewing sarcoma tumor growth. Conversely, KDM6B demethylated H3K27me3 at specific EWSR1::FLI1-active enhancers, colocalizing with BRG1 at GGAA repeats. Loss of KDM6B impaired the growth of Ewing sarcoma tumor xenografts. These results highlight KDM6 demethylases as EWSR1::FLI1 functional partners with potential as targets for treating Ewing sarcoma. KDM6A and KDM6B mediate critical mechanisms behind EWSR1::FLI1 transcriptional activation program involving demethylase-independent and dependent functions, respectively, supporting the development of therapeutic strategies targeting these demethylases in Ewing sarcoma.
2025-08-22 | Rare case of Infiltrative multifocal Ewing sarcoma presenting as neck mass.
Ewing sarcoma is a rare, highly aggressive small round cell tumor that primarily affects the bones of adolescents and young adults, with extra skeletal involvement being particularly uncommon. We present the case of an 18-year-old male with a progressively enlarging, painful swelling in the right posterior neck, ultimately diagnosed as Extra skeletal Ewing sarcoma involving the occipital bone and C1 vertebra. Imaging revealed extensive intracranial, intraspinal, and paravertebral extension with multiple skeletal metastases. Histopathological and immunohistochemical analysis confirmed the diagnosis, showing NKX 2.2 positivity. The patient was initiated on systemic chemotherapy using the VDC/IE regimen, leading to significant clinical and radiological improvement. This case underscores the importance of considering Ewing sarcoma in atypical paraspinal and cranial presentations and highlights the critical role of early multimodal imaging and chemotherapy in managing aggressive disease.
2025-05-26 | Transforming bone cancer treatment: a comprehensive review of green-synthesized metal nanoparticles.
Osteosarcoma (OS), chondrosarcoma (CHS), and Ewing sarcoma (EWS) are the main types of bone cancer (BC). OS is the most common BC in this group. It is most common in children and older people, especially in their long bones. Treatments for bone sarcomas and tumors have slowly improved, so researchers began looking into additional and alternative approaches to standard therapies. Therefore, the ability to precisely manipulate metallic nanoparticles (MNPs)' form, size, charge, and surface modification makes them very useful in treating bone cancer. However, due to the biocompatibility and possible toxicity of MNPs, MNP has limits for clinical use in treating BC. Therefore, the green synthesis of MNPs is achieved by bio-reducing metallic ions, which results in the creation of NPs, using living entities or their extracts. Green MNPs derived from natural sources provide a secure and environmentally responsible solution. Benefits of green MNPs include tailored medicine delivery and biocompatibility. Green MNPs reduce damage to healthy cells while improving the targeting of bone cancer cells. In this study, we reviewed how different MNPs synthesized using green methods can help treat various types of BC. This work reviewed the usual way of making MNPs for treating BC, the problems with this standard way of making MNPs, and the benefits and possible future uses of green synthetic MNPs for treating BC.
proteins
2026-01-03 | RUNX2 Represses the EWS-FLI1-mediated Transcription in Ewing's Sarcoma Cells.
Ewing's sarcoma is an aggressive pediatric malignancy driven by specific chromosomal translocations, predominantly leading to the oncogenic fusion protein EWS-FLI1. Runt-related transcription factors 1 and 2 (RUNX1 and RUNX2), which are key transcription factors involved in osteoblastic differentiation and skeletal morphogenesis, are not expressed in Ewing's sarcoma. Our study aimed to elucidate the relationship between the RUNX genes and EWS-FLI1. We used Ewing's sarcoma cell lines (A673 and NCR-EW2). EWS-FLI1 knockdown was achieved using shRNA, while inducible expression of RUNX1, RUNX2, EWS-FLI1, or EWS-ERG was performed using a Tet-on system. Gene and protein expression levels were quantitatively assessed by qPCR and Western blot analysis, respectively. Cell growth was evaluated using spheroid formation and cell viability assays. Truncated RUNX1 or RUNX2 constructs were employed to identify functional domains, with their intracellular localization confirmed by immunostaining. We observed low expression of RUNX1 and RUNX2 in Ewing's sarcoma cells. Notably, EWS-FLI1 knockdown increased RUNX2 gene expression. Conversely, inducible expressions of either RUNX1 or RUNX2 suppressed the expression of EWS-FLI1 target genes and inhibited cell proliferation and spheroid formation. Additionally, the RUNT domain of RUNX1 and RUNX2 was not essential for their inhibitory effect on EWS-FLI1 target gene expression. Importantly, both EWS-FLI1 and EWS-ERG down-regulated RUNX2 gene expression in hTert-RPE1 cells. EWS-FLI1 suppresses RUNX2 gene expression in Ewing's sarcoma cells, and re-expressing RUNX2 inhibits cell growth. These findings suggest that RUNX2 has a negative impact on the oncogenic process in Ewing's sarcoma.
2013-09-01 | Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL
Ewing's sarcoma (ES) associated with high osyeolytic lesions typically arises in the bones of children and adolescents. The development of multi-disciplinary therapy has increased current long-term survival rates to greater than 50% but only 20% for high risk group patients (relapse, metastases, etc.). Among new therapeutic approaches, osteoprotegerin (OPG), an anti-bone resorption molecule may represent a promising candidate to inhibit RANKL-mediated osteolytic component of ES and consequently to limit the tumor development. Xenogenic orthotopic models of Ewing's sarcoma were induced by intra-osseous injection of human TC-71 ES cells. OPG was administered in vivo by non-viral gene transfer using an amphiphilic non ionic block copolymer. ES bearing mice were assigned to controls (no treatment, synthetic vector alone or F68/empty pcDNA3.1 plasmid) and hOPG treated groups. A substantial but not significant inhibition of tumor development was observed in the hOPG group as compared to control groups. Marked bone lesions were revealed by micro-computed tomography analyses in control groups whereas a normal bone micro-architecture was preserved in the hOPG treated group. RANKL over-expressed in ES animal model was expressed by tumor cells rather than by host cells. However, TRAIL present in the tumor microenvironment may interfere with OPG effect on tumor development and bone remodeling via RANKL inhibition. In conclusion, the use of a xenogenic model of Ewing's sarcoma allowed discriminating between the tumor and host cells responsible for the elevation of RANKL production observed in this tumor and demonstrated the relevance of blocking RANKL by OPG as a promising therapy in ES.
2011-05-01 | Trail sensitivity in Ewing's sarcoma patients is modulated by the expression of death receptor 4 and its short isoform despite predominant dr5 level
Activation of cell surface death receptors by their cognate ligands triggers apoptosis. Several human death receptors (Fas, TNF-R1, TRAMP, DR4, DR5, DR6, EDA-R and NGF-R) have been identified. The most promising cytokine for anticancer therapy is TRAIL/APO-2L, which induces apoptosis in cancer cells by binding to death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. The cytotoxic activity of TRAIL is relatively selective to cancer cells compared to normal cells. Signaling by TRAIL and its receptors is tightly regulated process essential for key physiological functions in a variety of organs, as well as the maintenance of immune homeostasis. Despite early promising results, recent studies have identified several TRAIL-resistant cancer cells of various origins. Based on molecular analysis of death-receptor signaling pathways several new approaches have been developed to increase the efficacy of TRAIL. Resistance of cancer cells to TRAIL appears to occur through the modulation of various molecular targets. They may include differential expression of death receptors, constitutively active Akt and NFκB, overexpression of cFLIP and IAPs, mutations in Bax and Bak genes, and defects in the release of mitochondrial proteins in resistant cells. Conventional chemotherapeutic and chemopreventive drugs, and irradiation can sensitize TRAIL-resistant cells to undergo apoptosis. Thus, these agents enhance the therapeutic potential of TRAIL in TRAIL-sensitive cells and sensitize TRAIL-resistant cells. TRAIL and TRAIL-receptor antibodies may prove to be useful for cancer therapy, either alone or in association with conventional approaches such as chemotherapy or radiation therapy. This review discusses intracellular mechanisms of TRAIL resistance and various approaches that can be taken to sensitize TRAIL-resistant cancer cells.
2010-12-22 | Osteoprotegerin inhibitits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL produced by tumor cells
reduces it. Luciferase assays and co-immunoprecipitation revealed that Twist forms a transcription complex with NFkB through its RBD domain to activate IL-8 promoter. In addition, the DNA binding ability is also required for this activation. Furthermore, increases in IL-8 production elevated the invasive potential of Twist over-expressing cells through activation of metalloproteinase. Using IL-8 neutralizing antibodies and blockage of IL-8 receptors (CXCR1/2) activation resulted in decreased MMP9 production and activation, and subsequently decrease in invasive ability of Twist over-expression breast cancer cells. Collectively, our results demonstrate that Twist overexpression in breast epithelial cells promotes their transformation and enhances their invasive capabilities through IL-8 production.
2010-04-07 | Preclinical Evidence that Use of TRAIL in Ewing's Sarcoma and Osteosarcoma Therapy Inhibits Tumor Growth, Prevents Osteolysis, and Increases Animal Survival
Abstract Purpose: Osteosarcoma and Ewing's sarcoma are high-grade neoplasms typically arising in the bones of children and adolescents. Despite improvement in therapy, the five-year survival rate is only 20% for patients not responding to treatment or presenting with metastases. Among new therapeutic strategies, the efficacy of tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily with strong antitumoral activity and minimal toxicity to most normal cells and tissues, was investigated by complementary approaches both in vitro and in preclinical models. Experimental design: The sensitivity of osteosarcoma and Ewing’s sarcoma cell lines to TRAIL was investigated in vitro by determining TRAIL receptor expression together with TRAIL effects on cell viability and apoptosis. Complementary preclinical studies were carried out in respective tumor models by inoculation of osteosarcoma or Ewing’s sarcoma tumor cells in paraosseous location. In addition, a model of lung nodule dissemination was developed by i.v. injection of osteosarcoma cells. Results: In vitro, both osteosarcoma and Ewing’s sarcoma cells that express the TRAIL death receptors were highly sensitive to TRAIL-induced caspase-8–mediated apoptosis. TRAIL administered in vivo by nonviral gene therapy inhibited primary bone tumor incidence and growth by 87% and prevented tumor-induced osteolysis, leading to a significant 2-fold increase in animal survival 40 days after tumor induction. Furthermore, TRAIL inhibited tumor nodule dissemination in lungs and increased survival in an osteosarcoma model. Conclusion: These findings suggest that TRAIL is a promising candidate for the development of new therapeutic strategies in the most frequent malignant primary bone tumors. Clin Cancer Res; 16(8); 2363–34. ©2010 AACR.
antibodies
2026-01-10 | Age-Related Clinicopathologic Patterns in Ewing Sarcoma (FET::ETS Family): A Comparative Analysis of Pediatric and Adult Patients.
Background: Ewing sarcoma (ES) is a rare, aggressive small round cell sarcoma (SRCS) that peaks in adolescence. Given its rarity, atypical age or site presentations increase the risk of misclassification. This study examines age-related clinicopathological patterns in molecularly confirmed canonical ES (FET::ETS-fused). Methods: Between 2016 and 2025, 90 tumors diagnosed as ES or Ewing-like SRCSs underwent targeted RNA sequencing and/or EWSR1 break-apart fluorescence in situ hybridization. Patients were stratified into three age groups: 0-18, 19-39, and ≥40 years. Clinical, anatomical, pathological, molecular, and treatment/outcome variables were compared across strata. Results: Canonical ES accounted for 84% (76/90) of SRCSs, dominated by EWSR1::FLI1 (89%). ES comprised 91% of SRCSs in children but declined to 75% in older adults. Tumors arose mainly in bone (63%), with a significant age association (p = 0.016): children and young adults were primarily skeletal (73% and 62%), whereas older adults were predominantly extraskeletal (78%). Renal ES clustered in adults ≥40 years (p = 0.003). Classic histology predominated; atypical patterns were more common in extraskeletal tumors but lacked age specificity. Ewing-like SRCSs (n = 14), with heterogeneous or absent fusions, displayed a broader age distribution-including infants and older adults-and a marked extraskeletal predominance (86%, p = 0.001). Metastatic presentation strongly predicted inferior survival (p = 0.025). Treatment was multimodal, with neoadjuvant chemotherapy more frequent in children (90%, p = 0.029). Conclusions: Age significantly influences anatomic presentation and certain treatment choices in ES, whereas histology and survival remain broadly similar across groups. Age-linked extraskeletal trends reinforce the importance of routine molecular testing, particularly in underreported Middle Eastern populations.
2026-01-01 | Integrated Immunotherapy Target Atlas for Ewing Sarcoma
The purpose of this study was to convert ESS32 from a fusion-associated RNA signature into a compartment-aware immunotherapy target atlas. We integrated GEO transcriptomic cohorts with HPA-derived normal-tissue, protein, subcellular, and secretome information, together with published proteomic and surfaceome evidence, to assign each candidate to a practical therapeutic target class. Our goal was to generate a ranked, biologically interpretable candidate list with explicit validation requirements. In doing so, we asked four linked questions: which ESS32 and comparator genes are most enriched in Ewing tumor relative to skeletal muscle; which of these signals recur across supportive tumor, model, perturbation, or cross-sarcoma contexts; how normal-tissue and protein-level evidence reorder RNA-ranked candidates; and which candidates are most compatible with TCR/vaccine, antibody/ADC/CAR, radioligand, biomarker, or validation-first development paths.
2025-08-26 | Partial surgical excision of ewing sarcoma in the lower mandible of an 11-year-old boy with dental malocclusion.
Ewing sarcoma (ES) is an uncommon and aggressive tumor that primarily affects children and adolescents, peaking in incidence between the ages of 10 and 20. Although it most frequently occurs in long bones and the pelvis, its presence in the lower mandible is extremely rare, creating notable challenges in both diagnosis and treatment. This report details an 11-year-old boy from a low-income background who was diagnosed with Ewing sarcoma localized to the lower mandible. Initially, he presented with ongoing pain and swelling, which were mistakenly attributed to dental problems, resulting in a delayed diagnosis. Imaging studies identified a permeative bone lesion, which was confirmed through biopsy to be Ewing sarcoma with the EWSR1-FLI1 fusion gene. The patient underwent partial surgical excision followed by a chemotherapy regimen. Unfortunately, he developed neutropenia and septic shock during treatment, leading to his eventual death. This case highlights the diverse clinical presentations of Ewing sarcoma, stressing the necessity for heightened awareness of malignant conditions in pediatric patients. It also discusses the socioeconomic factors that can delay diagnosis, underscoring the importance of raising awareness in underserved areas. A multidisciplinary treatment approach is essential, along with careful monitoring for complications. This case exemplifies the challenges in diagnosing and managing Ewing sarcoma in atypical sites such as the mandible. It emphasizes the need for early symptom recognition, addressing socioeconomic disparities and implementing comprehensive care strategies to enhance patient outcomes in pediatric oncology.
2025-05-26 | Ewing Sarcoma Family of Tumors (ESFTs) of Renal Origin Presenting With Bone Metastases: A Case Report.
We report a unique case of a female patient in her fifth decade of life who presented with groin pain and was found to have a right kidney mass measuring approximately 8 cm, in addition to multiple bone metastases. Both the nephrectomy specimen and the bone biopsy were found to belong to the Ewing sarcoma family of tumors (ESFTs). This was confirmed by immunohistochemical studies and fluorescence in situ hybridization (FISH) showing EWSR1 gene rearrangement. Molecular analysis with next-generation sequencing (NGS) showed a type II EWSR1:FLI1 gene fusion. The patient's disease progressed rapidly, and she passed away approximately three months after admission. Although extremely rare in the kidney, ESFT should be considered in patients who present with clinically aggressive kidney tumors.
2025-03-19 | Prolonged atraumatic back pain in an adolescent female: Emergency department presentation of Ewing's Sarcoma.
Back pain and syncope are two common complaints encountered in the emergency department. However, prolonged atraumatic back pain in a pediatric patient should always be considered a "red flag" symptom. We describe a case of a 14-year-old female who presented to the emergency department with syncope and hypotension due to low back pain who was ultimately diagnosed with Primary Ewing's Sarcoma (ES) of the lumbar spine with extensive pulmonary metastasis. The diagnosis was expedited by the use of a bedside RUSH exam that identified an otherwise asymptomatic, unilateral pleural effusion. ES is the second most common primary bone malignancy in adolescents and young adults and unfortunately has a delayed diagnosis due to vague and non-specific symptoms. Survival rates of metastatic ES are still quite poor despite advances in therapies and treatments. This case emphasizes the importance of obtaining a focused history and physical exam, and how targeted point-of-care ultrasonography can aid in the diagnosis of rare and life-threatening conditions.
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2025-04-21 | Abstract 106: Growth-associated protein 43 (GAP-43): the link to Ewing sarcoma bone metastasis
Abstract Ewing Sarcoma (ES) is an aggressive pediatric tumor that arises in bone or soft tissues. ES bone metastases do not respond well to routine therapies and their frequency markedly increases upon disease recurrence, which results in a lower survival rate in patients with osseous metastases as compared to those with pulmonary dissemination. Our previous studies have determined that ES bone metastasis is initiated by hypoxia in the primary tumor site, which leads to the formation of polyploid tumor cells, the progeny of which, named HYP-4n cells, exhibit high levels of chromosomal instability. These cells metastasize almost exclusively to bone and are less sensitive to cytostatic agents. In this study, we demonstrate that HYP-4n cells exhibit an upregulation in several neuronal proteins, specifically growth-associated protein 43 (GAP-43), a membrane protein promoting axon growth in neurons and formation of microtubes connecting glioblastoma cells into invasive and therapy-resistant cellular network. Similar phenotype characterized by the presence of microtube-like cell-cell connections was also observed in ES HYP-4n cells. GAP-43 immunostaining in HYP-4n cells revealed a punctuated pattern along the protrusions that is similar to its localization in neurons. Western Blot analysis performed on HYP-4n cells revealed a membranous localization of GAP-43, which was not detectable in their normoxic diploid counterparts. The functional role of the GAP-43-positive protrusions in connecting HYP-4n cells was confirmed by the gap-junction permeable dye transfer between the cells and ion transfer detected by a patch clamp assay. DAPI staining also displayed nuclear fragments within the protrusions, suggesting the transfer of genetic material. The suppression of GAP-43 expression via siRNA was further shown to inhibit HYP-4n cell migration measured via transwell assay. In immunostained ES xenografts, GAP-43 expression was shown in HYP-4n primary and osseous metastatic tumors, with the highest membranous expression in the ES cells on the invading edge of the tumors. A similar pattern of expression of GAP-43 was noted in the human samples of ES bone metastases. This study indicates that GAP-43 is active in the membrane in HYP-4n cells and drives the formation of microtube networks promoting cell invasion. Further studies are required to prove directly the role of GAP-43 in ES bone metastasis and chemoresistance. Citation Format: Tyler Biermann, Nicholas Cohen, Yasmine Wazni, Stefano Vicini, Jason Tilan, Joanna Kitlinska. Growth-associated protein 43 (GAP-43): the link to Ewing sarcoma bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 106.
2023-09-23 | Oncomeric Profiles of microRNAs as New Therapeutic Targets for Treatment of Ewing’s Sarcoma: A Composite Review
Ewing's sarcoma is a rare type of cancer that forms in bones and soft tissues in the body, affecting mostly children and young adults. Current treatments for ES are limited to chemotherapy and/or radiation, followed by surgery. Recently, microRNAs have shown favourable results as latent diagnostic and prognostic biomarkers in various cancers. Furthermore, microRNAs have shown to be a good therapeutic agent due to their involvement in the dysregulation of various molecular pathways linked to tumour progression, invasion, angiogenesis, and metastasis. In this review, comprehensive data mining was employed to explore various microRNAs that might have therapeutic potential as target molecules in the treatment of ES.
2023-02-27 | Integrative analyses of bulk microarray data to discover genes, pathways, and immune infiltration characteristics associated with targeting of Ewing sarcoma
Abstract Purpose To explore transcriptome and immunological features of patients with Ewing sarcoma (ES) using all publicly available microarray data. Methods Data of 479 ES tissues were integrated and normalized. Gene expression, immune infiltration, and cancer-specific pathways were analyzed. Genes of interest were knocked down, followed by cell proliferation and colony formation assays. Results Consistent with the previous reports of differential expressed genes (DEGs) in ES, our analysis identified CCND1 , HMCN1 , and NKX2-2 were among the most highly expressed, while TWNC1 , MYBPC1 , and CKM were among the lowest expressed genes. GO, KEGG, and GSEA enrichment analysis identified that the DEGs related to bone and muscle functioning, those that contributed to crucial cellular, and metabolism pathways such as actin binding, apoptosis, TCA cycle, and cell cycle were also significantly enriched. Immune infiltration analysis discovered that many T cell subsets including CD4T, CD8 T, and Gamma delta T cells were highly infiltrated, while monocytes and B cells were less infiltrated in tumors. A total of 138 genes were both significantly up-regulated in tumors and associated with decreased survival, while 38 significantly down-regulated genes were associated with increased survival, many of which were previously reported as oncogenes and tumor suppressors in ES and other cancers. Silencing of four newly identified top ranked up-regulated genes with decreased survivals in ES inhibited proliferation and colony formation of ES cells. Conclusion This study may provide a clear representative transcriptome profile of ES, providing diagnostic biomarkers, pathways, and immune infiltrative characteristics targets for ES.
2019-09-27 | Tumour-Derived Extracellular Vesicles (EVs): A Dangerous “Message in A Bottle” for Bone
Several studies have shown the importance of Extracellular Vesicles (EVs) in the intercellular communication between tumour and resident cells. Through EVs, tumour cells can trigger cell-signalling molecules and shuttle exogenous information to target cells, thus promoting spread of the disease. In fact, many processes are fuelled by EVs, such as tumour invasion and dormancy, drug-resistance, immune-surveillance escape, extravasation, extracellular matrix remodelling and metastasis. A key element is certainly the molecular profile of the shed cargo. Understanding the biochemical basis of EVs would help to predict the ability and propensity of cancer cells to metastasize a specific tissue, with the aim to target the release of EVs and to manipulate their content as a possible therapeutic approach. Moreover, EV profiling could help monitor the progression of cancer, providing a useful tool for more effective therapy. This review will focus on all the EV-mediated mentioned mechanisms in the context of both primary bone cancers and bone metastases.
2018-02-13 | miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors.
Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73β, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73β. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73β axis in the context of these malignancies.
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Drug Discovery Landscape
20 orphan drug designations for Skeletal Ewing sarcoma.
20 orphan drug designations for Skeletal Ewing sarcoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Dinutuximab beta | antibodies | EMA | 2026-06-19 | — | Recordati Netherlands B.V. |
dinutuximab beta | antibodies | FDA | 2025-04-25 | — | Recordati Rare Diseases Inc. |
small molecule RBM39-degrader | small molecules | FDA | 2024-10-22 | — | SEED Therapeutics Inc. |
modified messenger RNA encoding USP6 | RNAs | FDA | 2024-09-26 | — | Merlin Biotech Inc. |
padnarsertib | small molecules | FDA | 2024-07-09 | — | Karyopharm Therapeutics Inc. |
2-(2-chlorophenyl)-5-hydroxy-8-((3S,4R)-3-hydroxy-1-methylpiperidin-4-yl)-4-oxo-4H-chromen-7-yl dihydrogen phosphate | small molecules | FDA | 2023-03-14 | — | Sumitomo Pharma America, Inc. |
Cu-64 anti CD99 | antibodies | FDA | 2021-01-05 | — | Advanced Imaging Projects, LLC |
a novel humanized bispecific XmAb T cell recruiting antibody cross-reactive to human and nonhuman primate STEAP1 and CD3 | antibodies | FDA | 2020-07-07 | — | Amgen, Inc. |
18-(p-[131I]-iodophenyl)octadecyl phosphocholine | small molecules | FDA | 2018-07-03 | — | Cellectar Biosciences, Inc. |
ganitumab | antibodies | FDA | 2017-03-21 | — | NantCell, Inc., a wholly-owned subsidiary of ImmunityBio, Inc. |
(E)-N¿-(1-(5-Chloro-2-hydroxy phenyl)Ethylidene)-3-((4-Methyl Piperazin-1-yl) Sulfonyl) Benzohydrazide Mesylate | small molecules | FDA | 2017-01-12 | — | Salarius Pharmaceuticals |
Small molecule Ewing Sarcoma breakpoint region 1/Friend leukemia virus integration 1 fusion protein inhibitor | small molecules | FDA | 2016-06-30 | — | Georgetown University |
ANA-conjugated dactunomycin nanoemulsion | small molecules | FDA | 2015-07-07 | — | NanoSmart Pharmaceuticals, Inc. |
antinuclear antibody conjugated liposomal doxorubicin | antibodies | FDA | 2015-02-03 | — | NanoSmart Pharmaceuticals, Inc. |
bi-shRNA furin and GMCSF Autologous Tumor Cell Vaccine | RNAs | FDA | 2014-10-22 | — | Gradalis, Inc. |
Efdispo | small molecules | FDA | 2013-01-15 | — | TDP Biotherapeutics, Inc. |
phosphorothioate antisense olignucleotide against EWS-Fli-1 | oligonucleotides | FDA | 2008-09-22 | — | The Cure Our Children Foundation |
Full Phosphorothioate Antisense Oligonucleotide against EWS-Fli-1 nanoparticles | oligonucleotides | FDA | 2008-09-22 | — | The Cure Our Children Foundation |
fenretinide | small molecules | FDA | 2007-02-01 | — | Cancer Research UK |
Liposomal N-Acetylglucosminyl-N-Acetylmuramly-L-Ala-D-isoGln-L-Ala -gylcerolidpalmitoyl | other | FDA | 1998-06-10 | — | Endorex Corp. |
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