Abstract 1850: MUC13-targeted PPNPs efficiently inhibited pancreatic tumor growth and influenced tumor immune surveillance

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, characterized by a dismal 5-year overall survival rate, primarily due to lack of early detection and limited effective treatment. Gemcitabine (GEM) is most effective therapy for pancreatic cancer (PanCa), but it only offers a marginal survival benefit of 6 months. A combination of Paclitaxel (PTX) albumin nano-formulation (Abraxane) and GEM has shown marginal improvement in PanCa treatment. This poor treatment response has been associated with desmoplastic stroma, microbiome effects, altered tumor microenvironment (TME), suppressive immune cells and PDAC-specific signaling pathways. Our research has demonstrated that MUC13 is highly overexpressed in PanCa and is associated with cancer progression and metastases. Considering these facts, we have generated an MUC13 antibody targeted nanoparticle formulation for tumor specific targeted delivery of paclitaxel using a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated poly(lactic-co-glycolic acid) nanoparticles (PPNPs) to improve therapeutic outcome of PanCa therapy. Our MUC13-targeted PPNPs (MUC13-PPNPs) showed enhanced cellular uptake of MUC13-PPNPs formulation in HPAF-II (MUC13+) compared with Panc-1 (MUC13) PanCa cells as determined by immunofluorescence. Further, our novel formulation effectively inhibits growth and metastatic phenotypes in MUC13+ cells as compared with MUC13- cells of PanCa in vitro. In our PanCa xenograft mouse model (HPAF-II + stromal cells), we found that PPNPs alone significantly inhibited growth of tumor (P < 0.05 when compared with control (PLGA) and treatment group PTX. Furthermore, the tumor volume of MUC13-PPNPs group was not only highly significantly lower than control PLGA and PTX (P < 0.05), but also lower than PPNPs alone group (P < 0.05) or control (P < 0.05). Our findings also demonstrated that PPNPs/MUC13-PPNPs synergize GEM therapy response in vitro and in vivo mouse models. Further, tumor tissue treated with PPNPs/MUC13-PPNPs demonstrate the downregulated expression of sonic hedgehog and other oncogenic signaling axis determined by qPCR, Western blots, and immunofluorescence analyses. Additionally, our nano formulation effectively reduced tumor volume in syngeneic orthotopic xenograft mouse model involving injection of KPC-Luc in C57Black/6 mice and target tumor-associated macrophages (TAM) by repolarizing M2 into M1 phenotype via inhibiting expression of M2 markers and an increase in M1 markers. In conclusion, we observed that our novel formulation has high therapeutic ability for achieving pancreatic tumor specific delivery PTX, synergize GEM therapy response and altered the tumor immune surveillance mechanisms. Thus, this unique approach can effectively enhance therapeutic efficacy main line chemotherapies and immune checkpoint immunotherapies. Citation Format: Vivek Kumar Kashyap, Neeraj Chauhan, Mohammed Sikander, Eswara N. Ghali, Fnu Shabnam, Rahul Tiwari, Sheema Khan, Bilal B. Hafeez, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. MUC13-targeted PPNPs efficiently inhibited pancreatic tumor growth and influenced tumor immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1850.