Abstract B096: A comparative assessment of selinexor with trabectedin or lurbinectedin in patient-derived xenografts (PDX) of dedifferentiated liposarcoma (DDLPS) highlights the effectiveness of their sequential or concomitant combination
Authors: Pasquali Sandro , Arrighetti Noemi , Zuco Valentina , Soffientini Cesare , Tortoreto Monica , Brich Silvia , Barisella Marta , Collini Paola , Fabbroni Chiara , Cingarlini Sara , Gronchi Alessandro , Stacchiotti Silvia , Sanfilippo Roberta , Zaffaroni Nadia 
Published: December 2023

Abstract
Introduction: Trabectedin or selinexor as single agent showed limited effectiveness in patients with metastatic DDLPS in clinical trials. We conducted a preclinical study on two patient-derived xenografts (PDXs) of DDLPS to test the activity of combined and sequential treatment with selinexor and trabectedin or lurbinectedin, following evidence of clinical benefit from a rechallenge to trabectedin after selinexor in two patients with metastatic DDLPS.
Methods: Two PDXs (LPS-BZ; LPS-NV) from two patients with primary localized DDLPS treated with surgery were established in SCID mice. These models represented the DD component of DDLPS and were histomorphologically and molecularly (by FISH and RNAseq) characterized for consistency with the originating clinical tumors. Antitumor activity of single-agent selinexor and either trabectedin or lurbinectedin as well as of the selinexor-trabectedin sequence and both selinexor-lurbinectedin sequence and combination was assessed. Drug activity was evaluated as maximum tumor volume inhibition percentage (max TVI%).
Results: The anti-cancer activity of a re-challenge to trabectedin following treatment with selinexor, which was observed in two patients, let to the design of in-vivo experiments on PDXs of DDLPS to investigate the activity of a sequential treatment with selinexor plus trabectedin/luribinectedin or their combination. The histomorphological and molecular characteristics of PDXs of DDLPS (LPS-BZ and LPS-NV) were confirmed to reproduce the clinical tumor. In the PDX model (LPS-BZ) with the faster growth rate (doubling time: 5 days), the sequence of selinexor followed by trabectedin was more effective (max TVI 61%) than each single-agent (maxTVI 46% and 33% for selinexor and trabectedin, respectively). A further experiment was conducted in a PDX model (LPS-NV) characterized by a slower growth rate (doubling time: 12 days) and results consistently showed a greater activity for the selinexor and trabectedin sequence (mTVI 73%) compared to selinexor (mTVI 53%) or trabectedin (mTVI 35%) alone. Finally, we tested lurbinectedin instead of trabectedin in the LPS-NV PDX model. The sequence selinexor and lurbinectedin (mTVI 81%) or their combination (mTVI 74%) showed a greater anti-tumor effect compared to single agent selinexor (mTVI 65%) or lurbinectedin (mTVI 24%). RNA-seq analysis of control and treated tumors is ongoing to investigate the determinants of the positive interactions between trabectedin/lurbinectedin and selinexor as a function of treatment schedule.
Conclusion: The combination of selinexor with either trabectedin or lurbinectedin in DDLPS showed anti-tumor activity. Further analyses are ongoing to investigate the mechanisms underpinning the interaction of these drugs.
Citation Format: Sandro Pasquali, Noemi Arrighetti, Valentina Zuco, Cesare Soffientini, Monica Tortoreto, Silvia Brich, Marta Barisella, Paola Collini, Chiara Fabbroni, Sara Cingarlini, Alessandro Gronchi, Silvia Stacchiotti, Roberta Sanfilippo, Nadia Zaffaroni. A comparative assessment of selinexor with trabectedin or lurbinectedin in patient-derived xenografts (PDX) of dedifferentiated liposarcoma (DDLPS) highlights the effectiveness of their sequential or concomitant combination [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B096.