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Principal Investigator: THOMAS D. SCHMITTGEN
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $203,188
Funding agency: National Cancer Institute
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.
Terms: <3' Untranslated Regions><3'UTR><3-D><3-Dimensional><3D><Acinar Cell><Aciner Cells><Acinus organ component><Acute><Age><Assay><Attenuated><Binding Sites><Bioassay><Biodistribution><Biological Assay><Biological Markers><Blood><Blood Reticuloendothelial System><Body Temperature Changes><Body Weight><Caerulein><Cancer Treatment><Cancers><Cell Line><Cell surface><CellLine><Ceruletid><Ceruletide><Cessation of life><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chronic><Clinic><Clinical><Colorectal Cancer><Combining Site><Data><Death><Death Rate><Dendrimers><Dendritic Compounds><Dendrons><Development><Diagnosis><Disease><Disorder><Dose><Duct><Duct (organ) structure><Early Diagnosis><Early treatment><Engineering><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Dysplasia><Epithelium><Event><Formulation><Functional RNA><Genes><Glycoproteins><Histology><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><In Vitro><In vivo analysis><Incidence><Individual><Intraepithelial Neoplasia><Intraepithelial Neoplasms><KO mice><KPC genetically-engineered mouse><KPC model><KPC mouse><KPC murine><KRAS(G12D)><KRASG12D><Knock-out Mice><Knockout Mice><LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre><LSL-KrasG12D/+;LSL-p53R172H/+;Pdx-1-Cre><Lesion><Libraries><Luc Gene><Luciferase Gene><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Mesenchymal><Metaplasia><Metaplastic Change><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Molecular Tumor Suppression><Murine><Mus><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Null Mouse><Oligo><Oligonucleotides><Oncogenesis><Operative Procedures><Operative Surgical Procedures><Outcome><PanIN><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic><Pancreatic Cancer><Pancreatic Duct Dysplasia><Pancreatic Ductal Adenocarcinoma><Pancreatic Ductal Dysplasia><Pancreatic Intraepithelial Neoplasia><Patients><Process><Prognosis><Prophylactic treatment><Prophylaxis><Publishing><Pulmonary Cancer><Pulmonary malignant Neoplasm><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><Reactive Site><Repression><Role><Strains Cell Lines><Surgical><Surgical Interventions><Surgical Procedure><Testing><Therapeutic><Toxic effect><Toxicities><Transfection><Treatment Effectiveness><Tumor Suppression><United States><Untranslated RNA><acinus><acute pancreatitis><ages><anti-cancer therapy><arm><attenuate><attenuates><bio-markers><biologic marker><biomarker><cancer initiation><cancer therapy><cancer-directed therapy><chemo/radiation therapy><chemotherapy and radiotherapy><cultured cell line><developmental><early detection><early therapy><effective therapy><effective treatment><efficacy study><epigenetically><high risk><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenicity><improved><in vivo evaluation><in vivo testing><lipid based nanoparticle><lipid nanoparticle><lung cancer><malignancy><miRNA><miRNA delivery><miRNAs><microRNA delivery><mortality rate><mortality ratio><nano formulation><nano particle><nano particle delivery><nano-sized particle><nanoformulation><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotherapeutic><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><noncoding><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oligos><pancreas duct dysplasia><pancreas ductal dysplasia><pancreatic malignancy><precancer><precancerous><premalignant><qRTPCR><radiation or chemotherapy><restoration><screening><screenings><social role><surgery><three dimensional><tumor><tumorigenesis><vector>