While only the 31st most common cause of cancer, pancreatic cancer is the fourth most common cause of cancer-related death in the US. Patients typically present with advanced disease that is notoriously refractory to chemotherapy. Despite decades of research, meaningful advancements in the therapeutic intervention of PDAC have been largely absent. In other oncologic indications, there have been several recent clinical successes in targeted tumor delivery of therapeutic payloads, and the first clinical product will likely be approved in the US in 2011. Therefore, the overall goal of this proposal is to develop a molecularly targeted viral vector based gene delivery agent for the treatment of pancreatic cancer. In order to maximize safety, efficiency of gene delivery, and specificity, we will employ the strategy of targeting the adeno-associated virus (AAV) to PDAC using a combination of transductional and transcriptional control. The multi-PI team of Drs. Kelly, French and Logsdon combines expertise from diverse areas of science. Dr. Kelly has identified a novel biomarker of PDAC (Plectin-1) and also a high affinity and specificity peptide that targets that biomarker. By engineering the AAV capsid to express the Plectin-1 targeting peptide, Dr. French has already demonstrated transductional targeting of AAV to PDAC. Additionally, Dr. Logsdon has identified a PDAC-specific promoter that will allow transcriptional control of the AAV. This proposal takes a multidisciplinary approach that spans the fields of radiology, oncology, virology and molecular imaging to engineer a therapy for PDAC that targets both primary and metastatic tumors. The Specific Aims are: 1) Generation of transductionally and transcriptionally targeted AAV vectors specific for PDAC. In this aim, we seek to develop a novel AAV vector with improved PDAC-specificity and improved PDAC transduction efficiency over wild-type AAV2 by combining the PTP transductionally-targeted capsid with transcriptional targeting using PDAC-restricted promoters. 2) Suicide gene therapy for PDAC. In this Aim, we will develop 3 transcriptionally and transductionally targeted AAVs that will induce apoptosis when expressed in pancreatic cancer cells: an apoptosis inducing peptide (KFAKFAK), a secreted PTP-targeted KFAKFAK to test for bystander effects and activated Caspase 3. 3) Comprehensive analysis of transductionally and transcriptionally targeted suicide gene therapy in stringent mouse models of human PDAC. Here, we will evaluate the new system in 3 different clinically relevant animal models, including models with primary and metastatic disease. We will also utilize a well-validated SPECT/CT imaging agent to evaluate endpoints such as tumor burden and tumor volume. The combined research/development project will result in new AAV-based systems for PDAC gene therapy with considerable potential for both pre-clinical research and translation to clinical applications.