A Potential microRNA-Based Therapy for Pancreatic Ductal Adenocarcinoma Using AAV-Mediated Delivery

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in United States with a median survival of 4-6 months, making it one of the most lethal human malignancies. It is usually not diagnosed until after the cancer has metastasized when the resulting disseminated tumors are resistant to all forms of conventional chemotherapy and radiotherapy. Activating mutations in the proto-oncogene KRAS are found in over 95% of PDACs and are believed to be a key initiating event for this type of cancer. Dysregulation of microRNAs (miRNAs) has been observed in all examined cancer subtypes and specific miRNAs are known to act as oncogenes and tumor suppressors. In an effort to understand the role of miRNAs in PDAC, we identified miRNAs that exhibited altered expression upon mutational activation of KRAS. Using multiple model systems including human pancreatic duct cells, mouse pancreas tissues, and zebrafish pancreatic tumors, we documented that oncogenic KRAS consistently leads to repression of the miR-143/145 cluster. Restoration of expression of these miRNAs fully abrogates the tumorigenic potential of human PDAC cell lines in subcutaneous xenograft assays. Based on these findings, we are now assessing the therapeutic efficacy of AAV-mediated delivery of miR-143/145 in clinically-relevant pre-clinical mouse models using a translatable delivery approach.