Strategies to improve therapy to pancreatic cancer with targeted-nanoparticle

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival of about 13% and 3% for those with metastatic disease. Even with the latest regimens such as NALIRIFOX the median overall survival is still less than 12 months. Patients respond poorly to chemotherapy and immunotherapy, and this problem has been attributed, in part, to the dense fibrosis that surrounds cancer epithelial cells, the presence of M2-polarized immunosuppressing macrophages, and the lack of tumor-infiltrating lymphocytes (i.e., an immune ‘cold tumor)”. We have identified a G-protein coupled receptor called the cholecystokinin-B receptor (CCK-BR) that is not found in the normal human (or mouse) pancreas but it is expressed in precancerous PanIN lesions of the pancreas and is over-expressed in pancreatic cancer, making it an ideal candidate for targeted therapy. Furthermore, the peptide gastrin that is the major ligand for the CCK-BR is present in the pancreas during embryogenesis but is silenced at 14-week of gestation and is not detected in the normal human pancreas. However, gastrin becomes reactivated during pancreatic carcinogenesis and stimulates PDAC growth by an autocrine mechanism. Studies have shown that downregulation of gastrin expression with RNAi inhibits growth of PDAC. We developed a biodegradable polyplex nanoparticle (NP) to deliver gastrin siRNA to PDAC. We rendered the NP target-specific to bind to the CCK-BR using click chemistry with a 10-amino acid peptide which enhances tumor uptake by receptor binding, internalization, and release of the NP in the endosome for downregulation of gastrin mRNA via the RISC RNAi complex. We have shown that this NP inhibits growth and metastases of PDAC in several orthotopic models of human PDAC in athymic nude mice. Using the immune competent genetically engineered mouse model with mutant Kras, we showed the NP remodeled the pancreas tumor microenvironment by decreasing fibrosis and decreasing immunosuppressive M2-polarized macrophages. Our NP was accepted into the NCI nanocharacterization Lab Cascade program and has thus far passed stability and toxicology testing for a pre-IND application. PDAC is such an aggressive cancer that monotherapy is no longer recommended for those with nonsurgical disease. We hypothesize that the CCK-BR targeted NP delivering the anti-gastrin siRNA payload will improve chemotherapy and immunotherapy efficacy in PDAC by decreasing fibrosis and altering the immunosuppressive nature of the PDAC tumor microenvironment. In this proposal, we will test this hypothesis by the following specific aims: 1) Evaluate the ability of the NP to improve chemotherapy uptake and efficacy to mice bearing orthotopic human pancreatic cancer. 2) Study whether the NP can remodel the PDAC tumor microenvironment to increase efficacy of immune checkpoint inhibitors in immune competent mice bearing syngeneic orthotopic PDAC. Since testing new agents for the treatment of PDAC will require the administration of the new agent combined with other FDA-approved drugs, the results of this project will provide our team the strategy needed to advance the NP to a Phase 1 clinical trial. Based on the project's specific aims and hypothesis, animal models—specifically mice—are required because the research targets biological complexities that cannot be replicated in a lab dish or computer model. Reasons for this mouse model include the following: 1) PDAC is characterized by a "cold" immunologic state and dense fibrosis that acts as a physical barrier to treatment. • Fibrosis and Uptake: The study aims to prove that the nanoparticle (NP) can decrease this fibrosis to allow chemotherapy to penetrate the tumor. This requires the architectural pressure of a living organ. • Immune System Interaction: You cannot study the "cold" nature of a tumor or the influx of CD8 T-cells without a functional, circulating immune system. • M2 Macrophages: The research specifically looks at how the NP alte Project Number: 1R21CA313071-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jill Smith | Institution: GEORGETOWN UNIVERSITY, WASHINGTON, DC | Award Amount: $401,115 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-J (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11353095