(P 272) A COMPARATIVE ASSESSMENT OF SELINEXOR WITH TRABECTEDIN OR LURBINECTEDIN IN PATIENT-DERIVED XENOGRAFTS (PDX) OF DEDIFFERENTIATED LIPOSARCOMA (DDLPS)

Objective: Clinical trials showed the limited efficacy of trabectedin or selinexor as single agent in patients with metastatic DDLPS. 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 anecdotal evidence of clinical benefit from a rechallenge to trabectedin after selinexor in two patients with metastatic DDLPS. Two patients affected by metastatic DDLPS were re-challenged to trabectedin after developing disease progression during treatment with selinexor and they did show a partial response to trabectedin.

Methods: Two PDXs (LPS-BZ; LPS-NV) from two primary localized DDLPS treated with surgery at Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Italy) 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. Firstly, we tested the anti-cancer activity of either selinexor or trabectin or their sequence (selinexor followed by trabectedin). Secondly, we considered luribinectedin, a trabectedin analogue, which we analyzed as single agent or together with selinexor, both in a sequential (selinexor-lurbinectedin) and concomitant sequence. Drug activity was evaluated as maximum tumor volume inhibition percentage (max TVI%).

Results: The anti-cancer activity of a re-challenge to trabectedin following selinexor 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 trabectedin/luribinectedin plus selinexor or their combination. The histomorphological and molecular characteristics of PDXs of DDLPS (LPS-BZ and LPS-NV) were confirmed to recapitulate the clinical tumors. 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 second 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 model. The sequence selinexor and lurbinectedin (mTVI 81%) or their concomitant combination (mTVI 74%) showed a greater anti-tumor effect compared to single agent selinexor (mTVI 65%) and 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.