Yondelis (trabectedin)

Here we provide the basis for further development of trabectedin/irinotecan for patients with ES by the international cooperative groups. ClinicalTrials.gov: NCT04067115 .

Targeted and molecular therapies in EWS show significant promise, particularly in rational combinations that exploit the tumor's dependence on EWS-FLI1-driven transcriptional dysregulation, DNA damage repair deficiencies, or survival signaling. Future research must prioritize biomarker-driven patient selection, integration of multiomics approaches, and multicenter prospective trials to translate these strategies into clinically meaningful improvements in EWS survival.

P2, N=16, Recruiting, Italian Sarcoma Group | Trial primary completion date: Dec 2025 --> Dec 2026

Sub-cohorts included patients receiving neoadjuvant therapy (n = 33), primary resection (n = 193), palliative first-line chemotherapy (n = 26), or a palliative salvage therapy with trabectedin (n = 22)...SLFN11 is a prognostic and potentially predictive biomarker in STS in the context of chemotherapy. Our results support a prospective validation, standardization of SLFN11 assessment, and consecutive clinical implementation.

P2, N=100, Recruiting, Italian Sarcoma Group | Trial primary completion date: Dec 2025 --> Dec 2026

P2, N=85, Recruiting, Grupo Espanol de Investigacion en Sarcomas | Not yet recruiting --> Recruiting

P2, N=48, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P1, N=18, Not yet recruiting, M.D. Anderson Cancer Center

Pharmacokinetics explain the difference of the MTD between the phase I study and in TRABTRAP. Experimental and clinical efficacy and tolerability of the combination between trabectedin and tTF-NGR supports the active randomized part of TRABTRAP.

P2, N=10, Completed, Mario Negri Institute for Pharmacological Research | Recruiting --> Completed

Consistent with the longer doubling time, PDES were more resistant to doxorubicin, etoposide and vincristine and ionising radiation (p < 0.0001) than cell lines. PDES were sensitive to mTKIs (cabozantinib, lenvatinib, and regorafenib), and trabectedin. The response of PDES to drugs in vitro reflects the clinical experience of patients. Models incorporating PDES cells may positively contribute to the preclinical pipeline.

We found that LY2835219 and trabectedin significantly alter the nuclear distribution of endogenous EWS::FLI1, disrupting and mislocalizing EWS::FLI1 hubs, respectively. Together, our results reveal new insights into the assembly and regulation of endogenous EWS::FLI1 hubs at an unprecedented resolution. The methodology developed here will be useful for characterizing the functional hubs of many regular and pathological TFs in the future.