Abstract LB264: Evaluating TRAP1 as a novel, potential therapeutic target in dedifferentiated liposarcoma
Authors: Roma Karna, Marina Capece, Qi Zhang, Sayumi Tahara, Patricia Sarchet, Giovanni Nigita, Paolo Fadda, Sydney Rentsch, Fernanda Costas Casal de Faria, Valerie Grignol, Carlo Croce, Raphael Pollock, Federica Calore
Journal: Cancer Research (2025)

Abstract Liposarcoma, a rare malignancy originating from adipose tissue, includes well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). While WDLPS exhibits indolent behavior, DDLPS is a more aggressive, high-grade subtype, 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 prognosis or recurrence. Current treatment relies primarily on radical surgery, often combined with non-specific chemotherapy, yielding poor response rates and severely affecting patients’ quality of life. The aggressiveness of DDLPS and lack of effective systemic therapies highlight an urgent need for novel therapeutic targets and approaches. Mitochondrial dysfunction is increasingly recognized as a key driver in cancer progression. Cancer cells often exploit altered mitochondrial function to support rapid cell proliferation, resist apoptosis, and metastasize. TRAP1 (TNF Receptor-Associated Protein 1), a mitochondrial chaperone of the Hsp90 family, regulates mitochondrial metabolism, oxidative stress, and apoptosis, making it a promising target in various cancers. However, its role in DDLPS remains poorly defined. We propose to investigate TRAP1 as a novel potential target for DDLPS, leading to novel future therapeutic strategies. Our preliminary data demonstrate significantly elevated TRAP1 protein expression in DDLPS compared to WDLPS patient-derived cell lines, suggesting its involvement in DDLPS pathogenesis. To explore its therapeutic potential, we silenced TRAP1 using siRNA and inhibited its activity with MitoQuinone (MitoQ), a mitochondria-targeted antioxidant evaluated in non-cancer clinical trials. TRAP1 silencing significantly reduced DDLPS cell proliferation, as shown by MTS assays, and increased cell death, confirmed by Annexin V/PI staining. Similarly, MitoQ treatment led to significant, dose- and time-dependent cytotoxicity in DDLPS cells, validated using a 3D spheroid model. We are currently elucidating TRAP1’s role in regulating ROS production and mitochondrial function in DDLPS. Silencing TRAP1 disrupts mitochondrial homeostasis, potentially altering ROS balance and oxidative stress. Using MitoQ, we aim to clarify how TRAP1 modulation impacts ROS dynamics, mitochondrial membrane potential (ΔΨm), and ATP levels, potentially inducing energy imbalance and electron leakage. These analyses will deepen our understanding of TRAP1’s role in DDLPS pathogenesis and therapeutic response. Finally, to establish TRAP1’s clinical relevance, we will evaluate its mRNA expression in Normal Adjacent Tissue (NAT), WDLPS, and DDLPS patient samples, correlating levels with recurrence rates and survival outcomes. This research could reveal molecular mechanisms driving DDLPS tumorigenesis, identify TRAP1 as a potential therapeutic target, and validate it as a potential prognostic biomarker, ultimately improving DDLPS treatment strategies. Citation Format: Roma Karna, Marina Capece, Qi Zhang, Sayumi Tahara, Patricia Sarchet, Giovanni Nigita, Paolo Fadda, Sydney Rentsch, Fernanda Costas Casal de Faria, Valerie Grignol, Carlo Croce, Raphael Pollock, Federica Calore. Evaluating TRAP1 as a novel, potential therapeutic target in dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB264.