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

Area of Science:

• Oncology
• Cancer Research
• Preclinical Models

Background:

• Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma.
• Effective treatment options for DSRCT are limited, necessitating the development of novel therapeutic strategies.
• Patient-derived xenograft (PDX) models offer valuable platforms for preclinical cancer research.

Purpose of the Study:

• To evaluate the efficacy of various cytotoxic and targeted anticancer agents against DSRCT using a novel PDX model.
• To identify promising drug combinations for DSRCT treatment.
• To investigate the molecular mechanisms underlying treatment response in DSRCT.

Main Methods:

• Establishment and characterization of a novel DSRCT patient-derived xenograft (PDX) model.
• In vivo assessment of single-agent and combination therapies, including doxorubicin, pazopanib, larotrectenib, trabectedin, vinorelbine, irinotecan, and eribulin.
• Analysis of tumor volume inhibition (TVI), tumor regrowth kinetics, and molecular markers (G2/M checkpoint proteins, transcriptome).

Main Results:

• Trabectedin demonstrated higher activity (max TVI, 82%) compared to doxorubicin, pazopanib, and larotrectenib (max TVI, 55-66%).
• Vinorelbine, irinotecan, and eribulin showed significant tumor growth inhibition (max TVI, 96-98%), but tumors regrew post-treatment.
• The combination of irinotecan plus trabectedin achieved complete responses, maintained throughout the study, and modulated key molecular pathways (G2/M checkpoint, E2F targets).

Conclusions:

• The DSRCT PDX model effectively recapitulates human DSRCT characteristics for preclinical drug evaluation.
• Irinotecan in combination with trabectedin shows significant and durable antitumor activity in a DSRCT PDX model.
• The combination of irinotecan and trabectedin warrants further clinical investigation for DSRCT treatment.