(P 273) COMPARISON OF A PATIENT-DERIVED XENOGRAFTS (PDX) OF MYXOID PLEOMORPHIC LIPOSARCOMA (MPL) AND PLEOMORPHIC LIPOSARCOMA (PL) HIGHLIGHTS THE EFFECTIVENESS OF ERIBULIN IN A PDX OF MPL

Objective: MPL is an ultra-rare sarcoma usually occurring in children and adolescents, which is characterized by mixed histological features of myxoid and pleomorphic liposarcoma, without either DDIT3 rearrangements or MDM2/CDK4 amplification. MPL is characterized by high risk of disease recurrence and lack of disease-specific therapeutic options other than those used for soft tissue sarcomas (STS). We successfully generated a PDX of MPL to comparatively assess the effectiveness of standard therapeutic options for STS as well as other anti-cancer agents that showed activity in dedifferentiated liposarcoma. Interestingly, drugs such as eribulin may have higher effectiveness in patients with pleomorphic liposarcomas compared to those affected by dedifferentiated liposarcomas. In addition, we exploited a PDX of PL to search for differential response to these treatments with respect to MPL.

Methods: A PDX from a primary locally advanced MPL was generated from a patient pretreated with doxorubicin plus ifosfamide (4 cycles) followed by ifosfamide monotherapy (3 cycles) plus radiotherapy (54Gy) and surgery. We also generated a PDX from a patient with primary localized abdominal pleomorphic liposarcoma of the mesenteric-retroperitoneal space who underwent surgery. These models were histomorphologically and molecularly (by RNAseq) characterized for consistency with the originating clinical tumors. Antitumor activity of single-agent doxorubicin, ifosfamide, trabectedin, eribulin and selinexor as well as the combination of doxorubicin plus ifosfamide was tested in each model. Drug activity was evaluated as maximum tumor volume inhibition percentage (max TVI%).

Results: PDXs of MPL and PL reproduce characteristics of the clinical tumors. In the PDX model of MPL, eribulin achieved complete tumor response in all treated PDX (max TVI 100%). Six tumors regrew after approximately 50 days from the end of treatment while a tumor demonstrated complete histopathological response at the end of the experiment. Although single-agent doxorubicin or ifosfamide (max TVI 87% or 94%, respectively) as well at their combination (max TVI 97%) showed meaningful activity, tumor growth restated after the end of treatment in all mice. Single agent trabectedin (max TVI 67%) and selinexor (max TVI 55%) had limited effectiveness. Conversely, the PDX model of PL showed different tumor responses to these same treatments with eribulin (max TVI 41%) showing almost negligible effect and similar findings were obtained with either selinexor (max TVI 42%) or doxorubicin (max TVI 25%). Single-agent trabectedin (max TVI 80%) or ifosfamide (max TVI 83%) effectively induced tumor response and the addition of doxorubicin to ifosfamide let to the highest tumor response (max TVI 89%), which resulted in tumor growth stabilization until the end of the experiment. The differences in tumor response to eribulin seem to rely on the ability of the drug to selectively induce programmed cell death in terms of both apoptosis and necroptosis in the MPL PDX but not in the PL PDX. Further analysis with RNA-seq is in progress to clarify the mechanisms underpinning the different responsiveness profiles.

Conclusion: To the best of our knowledge this is the first PDX model of MPL and this study suggests the potential relevance of eribulin for this disease. In addition, the comparison with a PDX model of PL highlights different response to treatment approaches, such as the first line treatment options for soft tissue sarcomas doxorubicin with or without ifosfamide. Further analyses are ongoing to understand the determinants of eribulin activity in MPL