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

ABSTRACT: Desmoplastic small round cell tumor (DSRCT) is a rare and incurable malignancy characterized by the oncogenic EWSR1-WT1 transcription factor. This study exploited a novel DSRCT patient-derived xenograft (PDX), which reproduces histomorphological and molecular characteristics of the paired clinical tumor, to comparatively assess the activity of cytotoxic and targeted anticancer agents. Anti-tumor effect was moderate for single-agent doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI): 55-66%] while trabectedin had a higher effect (max TVI: 82%). Single-agent vinorelbine, irinotecan and eribulin achieved a nearly complete tumor growth inhibition (max TVI: 96-98%), although tumors started to re-growth 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 almost completely abrogated the expression of proteins involved in the G2/M checkpoint preventing cell entrance in mitosis and induced apoptotic and necroptotic cell death. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220172 | GEO | 2023/05/29

REPOSITORIES: GEO

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

Project description:Desmoplastic small round cell tumor (DSRCT) is a rare and incurable malignancy characterized by the oncogenic EWSR1-WT1 transcription factor. This study exploited a novel DSRCT patient-derived xenograft (PDX), which reproduces histomorphological and molecular characteristics of the paired clinical tumor, to comparatively assess the activity of cytotoxic and targeted anticancer agents. Anti-tumor effect was moderate for single-agent doxorubicin, pazopanib and larotrectenib [maximum tumor volume inhibition (max TVI): 55-66%] while trabectedin had a higher effect (max TVI: 82%). Single-agent vinorelbine, irinotecan and eribulin achieved a nearly complete tumor growth inhibition (max TVI: 96-98%), although tumors started to re-growth 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 almost completely abrogated the expression of proteins involved in the G2/M checkpoint preventing cell entrance in mitosis and induced apoptotic and necroptotic cell death. 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.

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