Abstract A119: Designing tumor-targeting nanoparticles for the delivery of therapeutic payloads in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a minimal five-year survival rate. A hallmark of PDAC is the prevalence of oncogenic mutations in the KRAS gene, observed in more than 90% of the cases. The KRAS oncogene plays a critical role in disease initiation and progression, and its signaling network represents a major target for therapeutic intervention. Our previous studies have shown that the combination of MEK1/2 and CDK4/6 inhibitors facilitates vascular remodeling that augments drug delivery and T cell immune surveillance through induction of a senescence-associated secretory phenotype (SASP). While combined MEK1/2 and CDK4/6 inhibition can reduce tumor growth in preclinical models, it is not sufficient to produce long-term tumor responses, and the toxicities associated with MEK inhibitors have limited their clinical advancement. Here, we designed novel lipid nanoparticles (NPs) coloaded with the MEK1/2 and CDK4/6 inhibitors for enhanced anti-tumor efficacy. The incorporation of ionizable lipids into the NPs promotes stable encapsulation and triggers pH-dependent dissolution of the NPs, allowing endosomal rupture and cargo release into the cytosol. In vitro, the NPs inhibited the downstream effectors of the RAS signaling pathway, leading to enhanced SASP factor expression. In an orthotopic KPC PDAC model, the NPs exhibited tumor-homing capability, resulting in a greater reduction in the phosphorylation of the retinoblastoma protein (p-RB) and the proliferation marker, Ki67, compared to administration of the free drugs. To further achieve cell-specific delivery, the NPs were conjugated to a linear peptide with a high affinity for epidermal growth factor receptor (EGFR) —a receptor overexpressed in up to 85% of PDAC cells but not normal adjacent pancreas tissue. The targeted NPs contributed to a greater NP uptake compared to untargeted NPs, leading to an increase in SASP factor expression in vitro. Similarly, systemic administration of targeted-NPs was significantly more effective in tumor growth reduction, supported by the suppression of p-RB and Ki67, as compared to untargeted NPs or free drugs. In addition, treatment with the targeted NPs led to an increase in innate natural killer (NK) cell and dendritic cell (DC) infiltration and activation, which was not observed previously with MEK and CDK4/6 inhibitors. Importantly, the targeted NPs minimized lymphocytopenia, neutrophilia, and off-target effects on RAS signaling in the colon typically caused by these inhibitors following systemic administration. Therefore, PDAC cell-targeted NPs allow enhanced anti-tumor efficacy of RAS pathway inhibitors while minimizing toxicity that has constrained their clinical implementation. Given their versatile properties, NPs can be engineered to encapsulate other inhibitors, including the RAS (ON) inhibitors currently being evaluated in clinical trials for PDAC patients. Furthermore, we anticipate that these NPs can be rationally coupled with innate immunotherapies to achieve more robust and long-lived anti-tumor effects. Citation Format: Haruka Mori, Kelly D. DeMarco, Hadiya K. Giwa, Ronnie W. Dinnell, Griffin I. Kane, Chaitanya N. Parikh, Miranda B. Diaz-Infante, Marcus Ruscetti, Prabhani U. Atukorale. Designing tumor-targeting nanoparticles for the delivery of therapeutic payloads in pancreatic ductal adenocarcinoma 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 (18Suppl₃): Abstract nr A119.