Abstract B033: Targeting NELFE using antisense oligonucelotides reduces tumor burden and increases overall survival <i>in vivo</i>

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignances with a 5-year survival rate at around 13%. This dismal prognosis is, in part, due to the dense desmoplastic stroma and low vascularity of PDAC tumors, leading to inefficient uptake of therapeutics. The combination of FDA-approved ultrasound contrast agents called microbubbles (MBs), and focused ultrasound (FUS) has the potential to increase drug uptake in PDAC tumors. Our team has developed a novel therapeutic that loads antisense oligonucleotides (ASOs) onto MBs for targeted drug delivery in vivo. The ASOs have been designed to target the pre-mRNA transcript of Negative Elongation Factor E (NELFE), a protein that is upregulated in multiple tumor types, including PDAC. In vitro ASO-only treatment was sufficient in significantly reducing cell proliferation, cell migration, and colony formation in three PDAC cell lines. To investigate the effects of ASO+MBs+FUS treatment in vivo, we performed intrapancreatic orthotopic injections of KPC-4662 cells derived from the KPC mouse model (LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-1-Cre) into C57BL/6 mice and recorded tumor growth over time using bioluminescence imaging. Once tumors were established, we performed 6 rounds of ASO+MBs+FUS treatment across a 2-week timespan. Mice treated with ASO+MBs+FUS had a significant reduction in tumor burden and increased overall survival compared to mice treated with MBs+FUS alone. In conclusion, targeting NELFE using ASO+MBs+FUS can be a potential therapeutic strategy for PDAC patients. Citation Format: Brittany N. Ruiz, Alvaro Lucci, Laura M. Reynolds, Pongsakorn Choochuen, Corinne Wessner, Christine Wiktor, Sarah Hynd, Christoph Eckert, Meghan Grim, Avinoam Nevler, Harish Lavu, Charles Yeo, Matthias M. Gaida, Elda Grabocka, John Eisenbrey, Hien Dang. Targeting NELFE using antisense oligonucelotides reduces tumor burden and increases overall survival in vivo [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B033.