Effectiveness of irinotecan plus trabectedin on a desmoplastic small round cell tumor patient-derived xenograft.

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.

• Authors: Valentina Zuco, Sandro Pasquali, Monica Tortoreto, Stefano Percio, Valentina Doldi, Marta Barisella, Paola Collini, Gian Paolo Dagrada, Silvia Brich, Patrizia Gasparini, Marco Fiore, Michela Casanova, Anna Maria Frezza, Alessandro Gronchi, Silvia Stacchiotti, Andrea Ferrari, Nadia Zaffaroni
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 16 Issue 6 (06 01 2023) ISSN: 1754-8411 [Electronic] England
• PMID: 37158111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. Published by The Company of Biologists Ltd.

Chemical References

• Trabectedin
• Irinotecan
• eribulin
• Antineoplastic Agents

Topics

• Humans
• Trabectedin (therapeutic use, pharmacology)
• Irinotecan (pharmacology, therapeutic use)
• Desmoplastic Small Round Cell Tumor (drug therapy, pathology)
• Heterografts
• Antineoplastic Agents (therapeutic use)