Yondelis (trabectedin)

As a result, we identified Torin 2, talazoparib, and trabectedin as top 3 candidates with potent anti-Ewing sarcoma activity. Mechanistically, exogenous TGF-β1 was sufficient to induce resistance in tumor-only spheroids, whereas pharmacological inhibition of TGF-β1 signaling restored drug sensitivity in heterotypic spheroids. These findings establish the DCMiC platform as a low-cost, physiologically relevant system for modeling tumor-stroma interactions and enabling scalable drug discovery in clinically relevant contexts for Ewing sarcoma and other solid tumors.

Although trabectedin-olaparib combination reached the prespecified threshold for statistical significance for PFS (p<0.10), the benefit was marginal in the all-comers STS population. Nonetheless, patients affected by PARP1-expressing STS and uterine leiomyosarcoma derived substantial benefit from the combination, supporting further histology- and biomarker-driven investigation in these settings.

P=N/A, N=7, Terminated, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Completed --> Terminated; The study was terminated prematurely due to slow recruitment after inclusion of 7 patients (of initially planned 100 patients).

Trabectedin demonstrates low disease control rate in translocation-related sarcomas, including few MCS cases. Anti-angiogenic tyrosine kinase inhibitors, such as apatinib and pazopanib, demonstrate activity in chondrosarcoma, but MCS-specific data are lacking. IDH1 inhibition benefits conventional subtypes rather than MCS. Early immunotherapy experience is limited, but pathway-directed strategies targeting BCL2 and PI3K-mTOR warrant evaluation.

P3, N=550, Completed, Italian Sarcoma Group | Active, not recruiting --> Completed

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

The chemotherapy combination was overall well tolerated, with good preservation of patients' quality of life, and no life-threatening adverse events reported.This descriptive case series of trabectedin-irinotecan in DSRCT supports preclinical evidence of synergistic activity. The regimen was well tolerated and showed potential clinical benefit even in heavily pre-treated patients, providing a rationale for further studies to optimize dosing and explore early integration.

Conventional chemotherapy may be used, with doxorubicin and dacarbazine being active though yielding poor responses. Other active drugs with currently ongoing studies in SFT are eribulin and trabectedin...An area of recent investigation is immunotherapy, with an ongoing randomized trial comparing nivolumab + ipilimumab versus pazopanib in advanced rare soft tissue sarcomas, including SFTs. Despite its rarity and therefore the difficulty in performing prospective randomized trials with a large number of patients, many promising results in perioperative (radiotherapy) or in the metastatic (medical therapy) setting have been obtained. This review overviews the main characteristics and provides the current knowledge on standard therapies.

Strategies include: (1) Reprogramming M2 to M1 phenotypes using agonists (TLR, STING, CD40) or inhibitors (STAT3/STAT6); (2) Metabolic modulation (targeting glycolysis, fatty acid oxidation, glutaminolysis); (3) Blocking recruitment axes (CCL2/CCR2, CSF-1/CSF-1R, CXCL12/CXCR4); (4) Depleting M2-TAMs (e.g., trabectedin, CAR-T cells, M2pep-drugs); (5) Enhancing phagocytosis (anti-SIRPα/CD47, anti-SIGLEC)...However, the complexity of the glioma microenvironment and blood-brain barrier necessitate combination strategies for clinical translation. Further research is needed to optimize specificity and overcome challenges like compensatory pathways and drug delivery.

Furthermore, LUR significantly restrained the in vivo growth of iCCA cells in the CAM model. Our data indicate that TRB and LUR possess strong anti-proliferative and pro-apoptotic activities and could represent promising therapeutic agents for the treatment of iCCA.

The addition of olaparib to trabectedin potentiates the cGAS-STING pathway activation and the upregulation of NKG2DLs, while simultaneously counteracting the OCT4 overexpression. Therefore, sequential treatment with trabectedin and olaparib followed by NK/CIK immunotherapy represents a promising strategy against advanced sarcomas and warrants further investigation.

P2, N=29, Completed, University of Michigan Rogel Cancer Center | Trial completion date: Jan 2025 --> Sep 2024 | Active, not recruiting --> Completed