Ewing Sarcoma

Here, we describe two patients with EWSR1::PATZ1 sarcoma, of which one patient was initially misdiagnosed as synovial sarcoma and RMS on two occasions. These patients underscore the diagnostic challenges and therapeutic uncertainties surrounding EWSR1::PATZ1 fusion sarcomas, emphasizing the need for further large collaborative studies to establish optimal prognostic implications and management strategies for this rare entity.

Key findings were validated by CETSA, isothermal dose-response fingerprinting, co-immunoprecipitation, and ubiquitination assays. These results demonstrate that shogaol exerts dual cytotoxic effects through the PLK1/NPM1 axis, presenting a potential natural therapeutic approach for Ewing sarcoma.

These findings offer mechanistic insights for the rational design of next-generation IGF-1R inhibitors, suggesting that optimal candidates should integrate a hydrophobic core for engagement of the inactive state with strategically positioned polar or ionizable groups to effectively interact with the more electrostatically enriched active conformation. The online version contains supplementary material available at 10.1007/s40203-026-00668-7.

Our studies revealed DBD-α4 helix is crucial for cooperative binding of EWSR1::FLI1 at GGAA microsatellites. This binding underlies many aspects of genome regulation by EWSR1::FLI1, such as formation of topologically associated domains (TADs), chromatin loops, enhancers, and productive transcription hubs.

This case highlights the diagnostic challenges of primary intracranial Ewing-like sarcoma and its potential to present with severe and irreversible visual impairment. Early neuroimaging in patients with persistent seizures is essential to avoid diagnostic delay, and molecular confirmation remains crucial for future cases.

The patient received eight cycles of alternating VDC/IE (vincristine, doxorubicin, cyclophosphamide / ifosfamide, etoposide) chemotherapy, resulting in a significant reduction in the primary tumor and resolution of the IVC thrombus and skeletal metastases. This case underscores the utility of a multimodal approach, where neoadjuvant chemotherapy can effectively downstage even metastatic disease, facilitating surgical resection. However, the overall prognosis remains poor, particularly for metastatic presentations, highlighting the urgent need for more effective and less toxic therapeutic regimens.

Importantly, this synergistic interaction was tumor-specific and absent in non-malignant fibroblasts, indicating a favorable therapeutic window. Together, these findings highlight the mevalonate pathway as a targetable metabolic dependency in ES and demonstrate how physiologically grounded 3D models can uncover clinically actionable treatment strategies that remain hidden in traditional 2D systems.

We present an accurate, simple, cost-effective and easy clinical applicable tool to support risk-adapted therapeutic interventions. The limited number of employed patients warrants the need of larger cohorts for validation.

Moreover, while apoptosis is induced rapidly following drug treatment, the suppression of protein synthesis is prolonged and persists beyond drug removal, suggesting distinct early and late mechanisms of drug-induced toxicity. Collectively, these findings define a unique CDK1- and caspase-dependent apoptotic pathway in response to replication stress and offer new insights into the molecular basis of this therapeutic vulnerability in Ewing sarcoma.

Early comprehensive genomic profiling was essential for confirming this rare subtype. Despite transient responses to Ewing sarcoma regimens, rapid chemoresistance was observed, emphasizing the need for precise molecular diagnosis and novel therapeutic approaches.

These findings provide new insights into the molecular mechanisms underlying EWS metastasis. The online version contains supplementary material available at 10.1007/s10616-026-01001-y.

Further cell assay experiments confirmed that cells expressing individual fusion genes were more sensitive to the suggested drugs, and the key downstream genes were affected by our drugs. FusionTarget provides a unique foundation for developing therapeutics targeting fusion proteins.