Metastases are a major cause of pancreatic ductal adenocarcinoma (PDAC) mortality, accounting for as many as 90% of cancer-related deaths. Therapies specifically designed to inhibit the mechanisms of invasion that drive metastases are not currently utilized as part of PDAC treatment. We propose that targeting invasion and metastases by exploiting fundamental differences in cancer cell oxidative metabolism using pharmacological ascorbate (P-AscH?) can enhance therapy outcomes in PDAC. Our studies have shown that P-AscH? induces oxidative stress and cytotoxicity in PDAC vs. normal cells. These studies have also established that P- AscH? is a pro-drug for delivery of hydrogen peroxide (H2O2) in tumor cells in vitro and in vivo via its oxidation. Our group has shown that P-AscH? is safe and well tolerated in combination which radiation and chemotherapy, reduces metastases during treatment, and increases median survival from 6 months to 16 months. In the current application we will extend these studies both pre-clinically and clinically. The current proposal tests the hypothesis that P- AscH? can reduce metastatic disease in PDAC via H2O2-mediated inhibition of HIF-1?- induced EMT in the following Specific Aims: 1. Determine if P-AscH? suppresses the metastatic process via H2O2-induced inhibition of HIF-1? mediated EMT. EMT induced by hypoxia is proposed to be a critical event in PDAC metastases. HIF-1? mediates hypoxia responses and is overexpressed in PDAC. Stabilization and activation of HIF-1? triggers its target genes related to metastases, which correlate with many different cellular processes, such as proliferation, angiogenesis and EMT. Our preclinical and clinical data suggest that metastatic disease does not occur in patients treated with P-AscH? and that P-AscH? inhibits the metastatic process and tumor cell invasion. 2. Determine if decreased expression of H2O2-metabolizing enzymes (i.e., catalase) in metastatic PDAC cells mediates the increased sensitivity to P- AscH?. Our clinical data demonstrate that patients with hepatic metastases had disappearance of the lesions while being treated with P-AscH? combined with chemotherapy. Our preliminary data also demonstrate that ascorbate-induced cytotoxicity correlates with the cell's ability to metabolize H2O2 via catalase. 3. As part of a phase II trial, we will assess systemic parameters indicative of oxidative stress as well as determine if catalase expression correlates with responses to therapy when P-AscH- is combined with gemcitabine/nab- Paclitaxel. The main objective of the phase II trial will determine efficacy of P-AscH? combined with gemcitabine/nab-Paclitaxel as defined by an increase in progression free survival and/or overall survival. If we can rigorously demonstrate that P-AscH? induces preferential oxidative stress and subsequent inhibition of metastatic disease in human PDAC, then the results of this proposal will provide a foundation for the rational design of large scale phase III trials using this combined modality cancer approach for the treatment of advanced PDAC.