Abstract B129: Repurposed T-Box-Targeting Drug in Liposomal Formulation Shows Synergistic Efficacy Against PDAC

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, largely due to late diagnosis, limited therapeutic response, and its dense desmoplastic stroma, which limits drug penetration. To address the need for more effective treatments, we investigated a repurposed small-molecule inhibitor targeting T-box transcription factors (TBX2/TBX3), emerging drivers of PDAC progression. In PDAC, TBX factors promote extracellular matrix (ECM), stiffening and remodeling, enhancing invasion, survival, and chemoresistance. Because developing new drugs is costly and slow, repurposing an existing compound offers a faster translational path while enabling targeted disruption of a key transcriptional program underlying PDAC desmoplasia. Methods: The significance of TBX2/TBX3 was investigated in human PDAC cell lines using SA-β-gal assay, Annexin-V/PI staining, transwell invasion, immunocytochemistry, and western blotting. The lead compound (name withheld pending IP protection) from a high-throughput drug repurposing screen was evaluated for cytotoxicity using MTT assays in PDAC cell lines (PANC-1, BxPC-3) and non-malignant epithelial and stromal cells (HPNE, HPaSteC). To model the desmoplastic tumor microenvironment, we generated 3D pancreatic cancer spheroids from the co-culture of PANC-1 and HPaSteC cells and quantified treatment-induced changes using SpheroidSizer®. A liposomal formulation was produced using hydrogenated soybean phosphatidylcholine, cholesterol, and helper lipids via cross-flow mixing, followed by characterization of particle size, polydispersity index (PdI), and encapsulation efficiency (EE). Results: When TBX3 was stably knocked down, the cells underwent senescence and had reduced proliferative ability. Interestingly, TBX2 levels increased in the TBX3-knockdown PDAC cells, and depleting TBX2 in these cells inhibited their migration and invasion. These results demonstrated that TBX2 and TBX3 have distinct oncogenic functions in PDAC and that any effective anti-PDAC drug will need to inhibit them both. Treatment with drug X in 3D desmoplastic models showed that initial exposure caused limited penetration, damaging mainly the outer layers, resulting in shedding in an onion-like manner. Subsequent treatments resulted in deeper penetration and complete disruption of the spheroid core at higher concentrations. Conclusion: The repurposed compound shows strong cytotoxicity against PDAC cells and effectively disrupts desmoplastic 3D spheroids with repeated dosing. The successful development of liposomal formulation further supports its potential as a therapeutic candidate, warranting future evaluation—particularly in combination with other chemotherapies—for PDAC treatment. Citation Format: Susan Immanuel, Serala Karabo, Sharon Prince, Joshua Reineke. Repurposed T-Box-Targeting Drug in Liposomal Formulation Shows Synergistic Efficacy Against PDAC [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr B129.