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

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. Anti-tumor 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 a nearly complete tumor growth inhibition (max TVI: 96-98%), although tumors regrow after the end of treatment. 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 a reprogramming of DSCRT transcriptome with a downregulation of E2F targets, G2/M checkpoint, and mitotic spindle gene sets. This study emphasizes the importance of patient-derived pre-clinical models to explore new treatments in DSRCT and fosters clinical investigation in the activity of irinotecan plus trabectedin.