Abstract 6726: Effectiveness of irinotecan plus trabectedin in a desmoplastic small round cell tumor patient-derived xenograft

Desmoplastic small round cell tumor (DSRCT) is a ultra-rare pediatric scarcoma with poor overall survival. This tumor is dependent on the continued expression and activity of its pathognomonic molecular lesion, the EWS-WT1 transcription factor. DSRCT is often treated with multimodal approach of chemotherapy, surgery, and radiotherapy. Given the rarity of the disease, there have not been clinical studies to establish an effective therapeutic regimen. Indeed, the development of fully characterized preclinical models, able to reproduce the molecular characteristics of clinical tumors, appears instrumental for testing novel therapeutic strategies and accelerating the translation of preclinical findings to the clinical practice. In this study we exploited a novel DSRCT patient-derived xenograft (PDX), which reproduces histomorphological, genomic (CNV) and transcriptomic 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%], trabectedin had a higher effect (max TVI: 82%) while irinotecan and eribulin almost complete inhibited tumor growth (max TVI: 96% and 98%, respectively). Interestingly, combination of irinotecan with either eribulin or trabectedin resulted in complete responses which were maintained until the end of the experiment for irinotecan + trabectedin. The trabectedin + irinotecan combination markedly reduced the expression of anti-apoptotic proteins and caused caspase-3 cleavage, consistent with an apoptotic response, and also induced the accumulation of phospho-RIP1 (Ser166) and phospho-RIP3 (Ser227), indicating the occurrence of necroptosis, a type of programmed cell death with necrotic morphology. In line with these findings, transcriptomic profile analysis of ex-vivo tumor samples obtained from mice exposed to trabectedin ± irinotecan revealed a reduced expression of the biological pathways related to apoptosis and cell proliferation in tumor exposed to the drug combination. Mechanistically, we found that these effects were mediated, at least in part, by the down-regulation of EWS-WT1 chimeric protein and its downstream targets, as assessed by PCR and western blotting. Overall, 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, providing a step forward for developing more effective trabectedin-based combinations for DSRCT to be tested in clinical trials. Citation Format: Valentina Zuco, Sandro Pasquali, Monica Tortoreto, Stefano Percio, Valentina Doldi, Marta Barisella, Paola Collini, Gianpaolo Dagrada, Silvia Brich, Patrizia Gasparini, Marco Fiore, Michela Casanova, Anna Maria Frezza, Alessandro Gronchi, Silvia Stacchiotti, Andrea Ferrari, Nadia Zaffaroni. Effectiveness of irinotecan plus trabectedin in a desmoplastic small round cell tumor patient-derived xenograft. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6726.