R21 MPI microRNA directed therapy for treating early stage pancreatic cancer

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Project Summary Pancreatic ductal adenocarcinoma (PDAC) is currently the third most lethal cancer in the United States. It is currently the third leading of cancer-related deaths in the United States and by the end of this decade, pancreatic cancer is predicted to pass colorectal cancer, making it the second most lethal cancer in the USA, second only to lung cancer. The poor prognosis of pancreatic cancer is in part due to the late-stage diagnosis. Patients diagnosed with pancreatic cancer typically succumb to the disease within a year or less of initial diagnosis. New incidence and death rates from pancreatic cancer are almost identical, emphasizing the fact that nearly all patients diagnosed with pancreatic cancer will eventually die of the disease. Therefore, developing strategies to improve the early diagnosis and treatment of pancreatic cancer is critical. In mice, pancreatic cancer precursor lesions – pancreatic intraepithelial neoplasms or PanINs are preceded by the process of acinar ductal metaplasia (ADM). microRNA (miRNA) is a class of small noncoding RNAs that epigenetically regulate these processes. Our previous studies suggest the tumor suppression role of miRNAs encoded within the MIR217 host gene, i.e. miR-216a, -216b, and -217. These miRNAs are pancreas enriched with predominate expression in pancreatic acini but are reduced during the pre-malignant stages (ADM and PanIN) and in PDAC. Based on these discoveries, we hypothesize that restoration of miR-216a to the pancreas through an acinar cell-targeting nanoparticles (NPs) can shift the early-stage cancer lesion to the acinar state, reducing PanIN and PDAC formation. To test our hypothesis, we will optimize the nanoparticle formulation for efficient miRNA delivery to acinar cells by screening a library of dendrimer-lipid nanoparticles (DLNPs) formulations for high delivery potency, low toxicity, and low immunogenicity. The ability of NP-formulated miR-216a and NPs per se to inhibit in vitro ADM will be studied on an in vitro 3-D assay. DLNPs will be engineered to target glycoprotein 2 (GP2) a cell surface marker that is exclusively expressed by normal acinar cells and those acinar cells undergoing ADM. miR-216a oligos formulated into anti-GP2 DLNPs will be evaluated for maximally tolerated dose, toxicity, biodistribution, and efficacy. The majority of therapeutic approaches for pancreatic cancer are focused on late-stage treatment, however, early preventative therapeutics that may improve the clinical outcomes of PDAC patients have not been investigated. We investigate the potential of nanotherapeutics to target pancreatic acinar cells early before the onset of PDAC. If implemented into the clinic, this therapy will allow individuals with high risk of pancreatic cancer, as identified through a biomarker, to receive administration of treatment options at an earlier stage, leading to better clinical outcomes.