Abstract 557: TRAP1 represents a mitochondrial target and biomarker of dedifferentiated liposarcoma.

Abstract Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive adipocytic malignancy with a nearly 85% local recurrence rate, exceptionally high compared to other tumors, and a 10-year survival rate of only 10%. No reliable biomarkers currently predict recurrence or therapeutic response. Current management relies primarily on radical surgery, often combined with non-specific chemotherapy, which yields poor outcomes and severely compromises patients’ quality of life. The aggressiveness of DDLPS and the lack of effective systemic therapies highlight an urgent need for novel molecular targets and treatment approaches. We identified the mitochondrial chaperone TRAP1 (TNF Receptor-Associated Protein 1) as a potential oncogenic driver and therapeutic target in DDLPS. TRAP1 is a master regulator of mitochondrial metabolism, oxidative stress, and apoptosis, yet its role in DDLPS remains unknown. Our preliminary data show that TRAP1 protein and mRNA levels are significantly overexpressed in DDLPS compared to low grade well-differentiated liposarcoma (WDLPS) and Normal Adjacent Tissue (NAT), suggesting a contribution to tumor progression. To explore its therapeutic potential, we silenced TRAP1 using siRNA and inhibited its activity with MitoQuinone (MitoQ), a TRAP1 inhibitor currently evaluated in non-cancer clinical trials. TRAP1 silencing significantly reduced DDLPS cell proliferation and increased cell death, as shown by MTS assays and Annexin V/PI assays. MitoQ treatment led to significant, dose- and time-dependent cytotoxicity in DDLPS cells compared to their WDLPS counterpart, and impaired spheroid growth in 3D models. Moreover, TRAP1 knockdown significantly decreased mitochondrial membrane potential compared to control conditions, and triggered G1/S cell-cycle arrest, indicating disruption of mitochondrial function. Ongoing studies are investigating how TRAP1 modulation affects ROS production, mitochondrial dynamics and energy metabolism using Seahorse metabolic flux analysis, to define its contribution to metabolic reprogramming and redox balance in DDLPS. Finally, to establish TRAP1’s clinical relevance, we will assess TRAP1 mRNA expression in a larger cohort of liposarcoma patient samples to correlate its levels with recurrence rates and survival outcomes. This work positions TRAP1 as a mitochondrial therapeutic target and potential biomarker, offering novel mechanistic insight and paving the way for innovative DDLPS treatment strategies. Citation Format: Roma Karna, Esin Ulker, Sydney Rentsch, Marina Capece, Sayumi Tahara, Qi Zhang, Patricia Sarchet, Giovanni Nigita, Paolo Fadda, Fernanda Costas Casal de Faria, Valerie Grignol, Nicholas C. Denko, Carlo M. Croce, Raphael E. Pollock, Federica Calore. TRAP1 represents a mitochondrial target and biomarker of dedifferentiated liposarcoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 557.