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Effectiveness of irinotecan plus trabectedin on a desmoplastic small round cell tumor patient-derived xenograft.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2023 Jun 01; Vol. 16 (6). Date of Electronic Publication: 2023 Jun 14. - Publication Year :
- 2023
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Abstract
- This study exploited a novel patient-derived xenograft (PDX) of desmoplastic small round cell tumor (DSRCT), which reproduces histomorphological and molecular characteristics of the clinical tumor, to assess the activity of cytotoxic and targeted anticancer agents. Antitumor effect was moderate for doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI), 55-66%], while trabectedin had higher activity (max TVI, 82%). Vinorelbine, irinotecan and eribulin achieved nearly complete tumor growth inhibition (max TVI, 96-98%), although tumors regrew after the end of treatment. The combination of irinotecan with either eribulin or trabectedin resulted in complete responses, which were maintained until the end of the experiment for irinotecan plus trabectedin. Irinotecan-based combinations nearly abrogated the expression of proteins of the G2/M checkpoint, preventing cell entrance in mitosis, and induced apoptotic and necroptotic cell death. Consistently, irinotecan plus trabectedin resulted in reprogramming of DSCRT transcriptome, with downregulation of E2F targets, G2/M checkpoint and mitotic spindle gene sets. This study emphasizes the importance of patient-derived preclinical models to explore new treatments for DSRCT and fosters clinical investigation into the activity of irinotecan plus trabectedin.<br />Competing Interests: Competing interests V.Z., S. Pasquali, M.T., S. Percio, V.D., M.B., P.C., G.P.D., S.B., P.G., M.F., A.M.F., A.G., A.F. and N.Z. have no competing or financial interests. M.C. is on Advisory Boards for Pfizer, Bayer, Astra Zeneca, Servier and BMS. S.S. receives institutional research funding from Amgen Dompe, Advenchen, Bayer, Blueprint Medicines, Deciphera, Eli Lilly, Epizyme, Daiichi Sankyo Pharma, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks and Hutchinson MediPharma International Inc.; has received honoraria from Aadi, Bayer, Deciphera, Daiichi, Eli Lilly, Maxivax, Novartis, GSK and PharmaMar; and participates in a Data Safety Monitoring Board or Advisory Board for Bayer, Bavarian Nordic, Deciphera, Eli Lilly, Daiichi, GSK, Ikena, Maxivax, Novartis and Pharmamar.<br /> (© 2023. Published by The Company of Biologists Ltd.)
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 16
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 37158111
- Full Text :
- https://doi.org/10.1242/dmm.049649