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Dinutuximab beta effectively treats Ewing sarcoma when combined with chemotherapy

ABSTRACT: Ewing sarcoma is a rare and aggressive cancer of the bone and soft tissues that mainly affects children and young adults. Despite intensive multimodal therapy, the prognosis of patients with metastatic or recurrent disease remains poor. Therefore, novel therapeutic approaches are needed to improve the outcomes of patients with Ewing sarcoma. The disialoganglioside GD2 is highly expressed on Ewing sarcoma cells, making this tumor eligible for treatment with Dinutuximab beta, a monoclonal antibody targeting this antigen. Through in vitro and in vivo approaches, this study demonstrated that Dinutuximab beta effectively suppressed tumor growth by 60% (p=0.0135 vs vehicle) and improved survival rate by 68% (p=0.0006 vs vehicle) in a mouse model xenograft. The combination therapy with doxorubicin demonstrated superior efficacy compared to monotherapy, with enhanced tumor suppression (86%; p=0.0009 vs vehicle) and an extension of survival rate (146%; p=0.000025 vs vehicle). Overall, this study showed that Dinutuximab beta is effective against Ewing sarcoma, especially in combination with the standard induction chemotherapy regimen for this tumor. Integrating Dinutuximab beta into the standard chemotherapy regimen for Ewing sarcoma offers a promising new therapeutic approach that can potentially improve the prognosis for patients with high-risk disease, offering a more effective alternative to existing treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310619 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

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Dinutuximab beta effectively treats Ewing sarcoma when combined with chemotherapy

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