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.

Here, we performed a synthetic lethal drug screening in an approved drug library with ARID1A isogenic CRC cell lines and identified estramustine phosphate sodium (EMP), an FDA approved antimicrotubule chemotherapy drug, as a synthetic lethal partner of ARID1A...Furthermore, we identified that MAP4 is phosphorylated by PI3K, which is activated by ARID1A loss. These findings highlight MAP4 as a key regulator of microtubule dynamics in ARID1A-deficient cells and unveil a novel synthetic lethality relationship between ARID1A and EMP.

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).

Bulk and single-cell RNAseq followed by functional validation and in silico analysis showed that CLF treatment is associated with apoptosis, ER stress, oxidative phosphorylation, and mitochondrial dysfunction. Most importantly, CLF modulates the expression of several non-coding RNAs, including MALAT1 and NEAT1, that are linked to tumor cell proliferation, cell migration, and drug resistance.

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

P1, N=1, Enrolling by invitation, Vancouver Coastal Health

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.

Recently, our laboratory reported the dephosphorylation action of these nucleotidases toward the metabolites of clinically used nucleoside analog drugs, including gemcitabine, emtricitabine, tenofovir, and acyclovir. Using in vitro incubations and enzyme kinetics, we demonstrate the involvement of NT5C3 in the dephosphorylation of an important antineoplastic agent, fludarabine. Furthermore, we employed mass spectrometry imaging to visualize peptides corresponding to NT5C3 and other major nucleotidases in the kidney cortex and colonic mucosa.

P4, N=140, Not yet recruiting, Zhongshan Hospital, Fudan University; Zhongshan Hospital, Fudan University