Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Dr. David Oupicky

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a rare cancer with 66,440 new cancer cases and 51,750 estimated cancer deaths in the United States as of 2024, according to the American Cancer Society. The incidence rate of pancreatic cancer in the US for both sexes combined is 13.4 per 100,000 per year and is steadily increasing. With a 5-year survival rate of only 13% for all stages of PDAC, pancreatic cancer ranks third among cancer-related causes of death in the US and is expected to rise to the number two position by 2030. The detection of PDAC at an early stage has always been challenging, and hence, 90% of cases diagnosed are already at advanced and metastatic stage. The treatment options after diagnosis are also minimal. Even though there are several options ranging from chemotherapy to radiotherapy to targeted therapy, surgery remains the best and only curative treatment for PDAC, with several drawbacks. Efforts are being actively made to diagnose early and to develop a less invasive and more promising targeted therapy for PDAC. Immunogenic cell death (ICD) is a particular type of apoptosis pathway that can serve as a promising tool for pancreatic cancer treatment and prevent its recurrence later in life. Thus, an immunostimulator and delivery of mRNA for the protein, that can initiate the ICD pathway in the immunosuppressive tumor microenvironment, can be a potential approach to treat PDAC. In this dissertation research, I hypothesized that R848 (resiquimod; a TLR7/8 agonist) and recombinant mRNA for calreticulin (CALR)-loaded lipid nanoparticles could express this protein on the surface of the PDAC tumor cells, which while acting as “eat me” signal to the dendritic cells (DCs) for phagocytosis will also inducing the ICD response and simultaneously activate T cells to cytotoxic T cells and memory T cells to achieve enhanced combinational cancer therapy. To explore this hypothesis, the dissertation first discusses the nature of pancreatic cancer and its types, its risk factors, available treatment strategies, and the challenges linked to it. It then highlights immunotherapy as a growing field and discusses its advantages, and how it can be used as a promising treatment strategy for PDAC in the future. The development of lipid nanoparticles (LNP) for mRNA delivery has also been described with a special emphasis on its safety, enhanced tissue penetration, and efficiency especially when administered intraperitoneally, making it ideal for targeting solid tumors. Subsequently, in vitro findings demonstrate how an engineered mRNA led to CALR expression only on the cell surface of PDAC cells. This expression triggered phagocytosis and promoted apoptosis in the neighboring tumor cells. These findings were crucial evidence of the supporting hypothesis for the PDAC therapeutics. These findings were further validated in an in vivo system for which the C57BL/6 mouse model was utilized. The combination of FI-3/mCALR-Daf1 and R848 significantly reduced the tumor burden enhanced the immune cell infiltration, induced tumor apoptosis, remodeled tumor microenvironment, and modulated cytokine profile. These outcomes suggest that combinational therapy represents a promising and innovative treatment strategy for PDAC.

Comments

2025 Copyright, the authors

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Available for download on Thursday, April 29, 2027

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