(P 52) VALIDATION OF SYNGENEIC MURINE DEDIFFERENTIATED LIPOSARCOMA MODELS FOR PRECLINICAL EVALUATION OF THERAPEUTIC SENSITIVITY

Objective: Dedifferentiated liposarcoma (DDLPS) is a high-grade soft-tissue sarcoma with significant clinical challenges. Doxorubicin is the standard systemic therapy, yet fewer than 30% of patients respond effectively. This study examines chemotherapeutic sensitivity and transcriptional response in murine and human DDLPS models and assesses in vivo efficacy in an immune-competent mouse model to inform patient treatment strategies.

Methods: Adipocyte-CreTrp53f/f;Ptenf/f (ACPP)-derived DDLPS murine (N1011, N1018, N1343) and human (LPS141, DDLS8817) DDLPS cell lines, along with control murine mesenchymal stem cells (3T3), were tested with doxorubicin, selinexor, trabectedin, and dacarbazine to calculate IC₅₀ values using CyQUANT assays. Gene expression of p21 and Cdk4 in untreated and treated cells was assessed by qRT-PCR. For in vivo studies, N1011 cells were injected into C57BL/6 mice and treated with PBS, 1 mg/kg, or 4 mg/kg doxorubicin thrice weekly.

Results: Doxorubicin was consistently effective in all DDLPS lines (IC₅₀ ~230–460 nM), with 3T3 controls less sensitive. Selinexor demonstrated selective activity in N1011 (IC₅₀ = 400 nM), while trabectedin showed moderate efficacy (IC₅₀ = 500–750 nM), and dacarbazine was effective only in N1011. Doxorubicin reduced p21 and Cdk4 expression, notably in N1011 (40% p21 decrease). In vivo, 4 mg/kg doxorubicin significantly slowed tumor growth compared to control and 1 mg/kg.

Conclusion: Murine and human DDLPS cell lines show consistent doxorubicin sensitivity and transcriptional changes in cell cycle genes. N1011 cells were also uniquely sensitive to selinexor and dacarbazine, with moderate sensitivity to trabectedin observed in murine cell lines. The in vivo validation using a syngeneic murine model highlights its relevance for further mechanistic studies and the development of rational drug combination strategies in DDLPS.