Skeletal Ewing sarcoma: Research & Drug Discovery Data

Drug discovery

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].

Population

Age: Peak incidence at 10–20 years; 80% of cases occur under age 20 [7][11][15].
Gender: Male predominance (1.6:1) [7][11].
Race/Ethnicity: 9x higher incidence in White vs. Black populations; rare in Asian/African groups [2][11][14].

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

810 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:

2026-05-01 | Disulfidptosis-related genes define a prognostic signature and novel therapeutic targets in Ewing's sarcoma through transcriptomic analysis and experimental validation.

Ewing's sarcoma (ES) is a malignant osseous neoplasm characterized by a dismal prognosis, particularly in its metastatic variant. The significance of disulfidptosis-a newly identified cell death mechanism induced by cystine metabolic imbalance and mitochondrial dysfunction-has yet to be investigated in ES. Thus, the aim of this study was to assess the prognostic significance of disulfidptosis-related genes (DRGs) in this disease. We analyzed four GEO datasets to examine nine DRGs through differential expression, co-expression networks, and functional enrichment analyses. A predictive risk signature was developed using unsupervised clustering, Cox regression, and LASSO. Drug sensitivity was predicted using the GDSC database, and immune infiltration was quantified by ssGSEA. Single-cell RNA sequencing data was analyzed to explore DRGs distribution and functional heterogeneity. Molecular docking simulations were performed to evaluate interactions between DRGs and chemotherapeutic agents. Experimental validation of key DRGs was conducted in RD-ES cells using PCR and Western blotting, followed by functional studies of NDUFA11 via siRNA knockdown, assessing proliferation, migration, and invasion. Eight of nine DRGs were dysregulated in ES tissues. A five-gene risk model (NDUFS1, LRPPRC, NDUFA11, OXSM, NUBPL) stratified patients into high- and low-risk groups with significantly different survival outcomes. The risk score was an independent prognostic indicator. Drug sensitivity analysis revealed enhanced response to microtubule inhibitors in the low-risk group. Single-cell analysis demonstrated predominant enrichment of these five DRGs in malignant ES cells. NDUFA11-high malignant cells exhibited distinct metabolic and signaling pathway enrichment and stronger intercellular communication with the tumor microenvironment. Molecular docking confirmed stable binding between DRGs proteins and chemotherapeutic compounds. Experimental validation confirmed dysregulation of all five DRGs at both RNA and protein levels in RD-ES cells. Functional studies revealed that NDUFA11 knockdown significantly suppressed ES cell proliferation, migration, and invasion. This study provides the first prognostic signature connected to disulfidptosis for ES. Functional validation of NDUFA11 highlights its oncogenic role and potential as a therapeutic target. Single-cell analysis further elucidates the metabolic heterogeneity and microenvironmental interactions underlying ES progression.

Open article ↗

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.

Open article ↗

2026-03-04 | Favourable outcomes of extraskeletal Ewing sarcoma treated on a non-dense chemotherapy backbone with inclusion of radiotherapy for local control.

Extra skeletal Ewing sarcoma (EES) has less clearly defined clinical behaviour and treatment strategies. We report the clinical profile, outcomes and prognostic factors of children with EES treated at a single centre over a decade on a non-dose chemotherapy backbone. Children ≤15 years of age with EES treated from January 2012 to December 2021 were retrospectively analysed. All received EFT-2001, a non-dose chemotherapy protocol. Local therapy was planned after 9-12 weeks of chemotherapy. One hundred and six patients formed the study cohort. The majority of the primary was axial in location. Metastasis was present in 25.5%, mainly in the lungs. Local therapy was definitive radiotherapy in 59.1% (n = 58), surgery only in 3% (n = 3) and surgery and radiotherapy in 37.9% (n = 37). At a median follow-up of 43 months (range, 33-52 months), 4-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 70.4% (95% CI: 60.8%-85.3%) and 86.5% (95% CI: 79.3%-94.1%). Four-year EFS and OS of the localised cohort were 73.8% (95% CI: 60%-83.3%) and 88.6% (95% CI: 87.4%-90.2%) and those of the metastatic cohort were 32.4% (95% CI: 21.4%-86.5%) and 61.9% (95% CI: 54.1%-86.3%), respectively. On multivariate analysis, EFS was affected by albumin ≤ 3 g/dL (p = 0.01) and delay in any type of local therapy from initiation of chemotherapy ≥12 weeks (p = 0.01), whereas OS was affected by male gender (p = 0.02). Survival of children with EES treated on a strategy based on non-dose dense chemotherapy with inclusion of radiotherapy as local control modality is comparable to the Western cohorts, especially in the localised setting. Timely delivery of local therapy is imperative for optimal outcomes.

Open article ↗

2026-05-01 | Disulfidptosis-related genes define a prognostic signature and novel therapeutic targets in Ewing's sarcoma through transcriptomic analysis and experimental validation.

Open article ↗

2026-04-03 | Abstract 5426: Anatomic origins of primary skeletal tumors effect metastatic and prognostic behaviors.

Open article ↗

2026-03-04 | Favourable outcomes of extraskeletal Ewing sarcoma treated on a non-dense chemotherapy backbone with inclusion of radiotherapy for local control.

Open article ↗

Access all drug discovery articles and probability of success in trials forecasts:

Request access

Drug Discovery Landscape

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.
Full Phosphorothioate Antisense Oligonucleotide against EWS-Fli-1 nanoparticles	oligonucleotides	FDA	2008-09-22	—	The Cure Our Children Foundation
phosphorothioate antisense olignucleotide against EWS-Fli-1	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.

Skeletal Ewing sarcoma

Skeletal Ewing sarcoma

Skeletal Ewing sarcoma

Overview

Population

Burden

Therapies

Categories: rare bone diseases, rare neoplastic diseases

Research Papers

2026-05-01 | Disulfidptosis-related genes define a prognostic signature and novel therapeutic targets in Ewing's sarcoma through transcriptomic analysis and experimental validation.

2026-04-03 | Abstract 5426: Anatomic origins of primary skeletal tumors effect metastatic and prognostic behaviors.

2026-03-04 | Favourable outcomes of extraskeletal Ewing sarcoma treated on a non-dense chemotherapy backbone with inclusion of radiotherapy for local control.

2026-05-01 | Disulfidptosis-related genes define a prognostic signature and novel therapeutic targets in Ewing's sarcoma through transcriptomic analysis and experimental validation.

2026-04-03 | Abstract 5426: Anatomic origins of primary skeletal tumors effect metastatic and prognostic behaviors.

2026-03-04 | Favourable outcomes of extraskeletal Ewing sarcoma treated on a non-dense chemotherapy backbone with inclusion of radiotherapy for local control.

Drug Discovery Landscape

Updated: Aug 30, 2026