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Purpose: Pancreatic cancer continues to pose an enormous challenge to clinicians and cancer scientists. Clinical studies show that tumor necrosis factor-related apoptosisinducing ligand (TRAIL) exerts a potent and tumor-specific proapoptotic activity. However, most pancreatic cancer cells are resistant to TRAIL therapy. Human somatostatin receptor gene 2 (hSSTr2) is lost in 90% of pancreatic carcinoma. Oncolytic viruses are able to selectively lyse cancer cells and represent a promising novel anticancer therapy. Here, we investigated whether oncolytic adenovirus-mediated reexpression of hSSTr2 would enhance TRAIL-induced antitumor efficacy against pancreatic cancer. Experimental Design: The antitumor efficacies of combined or single treatment of hSSTr2 and TRAIL mediated by oncolytic adenovirus were compared in pancreatic cancer cell culture and xenografts. The mechanisms involved in hSSTr2-induced sensitization to TRAIL were studied. Results: Oncolytic adenovirus-mediated reexpression of hSSTr2 potentiated TRAILinduced tumor growth inhibition in vitro and in vivo. Reexpression of hSSTr2 augmented TRAIL-induced apoptosis against pancreatic cancer cells via up-regulation of death receptor 4 and down-regulation of Bcl-2. Conclusions: hSSTr2 restoration mediated by oncolytic adenovirus enhances TRAILinduced antitumor efficacy against pancreatic cancer. Combined treatment with oncolytic adenovirus-mediated hSSTr2 and TRAIL gene provides the rationale for a clinical trial in pancreatic cancer. (Clin Cancer Res 2009;15(16):5154-60) Pancreatic cancer is among the most lethal cancers. The median survival is less than 6 months with a 5-year survival rate of less than 5% (1). Despite intensive protocols, treatment resistance of pancreatic cancer greatly contributes to the poor prognosis of this disease (2, 3). The development of novel and improved therapeutic approaches is necessary.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is emerging as an attractive anticancer agent because of cancer cell specificity and potent antitumor activity. On binding to the death receptors 4 (DR4) and 5 (DR5), TRAIL initiates aggregation of the receptors and activates initiator caspase-8, which in turn initiates a protease cascade that activates downstream effector caspases, including caspase-3. Besides this extrinsic apoptotic pathway, TRAIL can also trigger apoptosis via intrinsic/mitochondrial pathway, in which TRAIL induces release of cytochrome c and regulates other mitochondrial factors, leading to formation of the apoptosome and activation of caspase-9 and caspase-3 (3, 4). August 11, 2009; DOI: 10.1158/1078 Soluble TRAIL and agonistic antibodies against the human death receptors are currently in clinical trials (5, 6). However, previous studies and our own data here show that the majority of pancreatic carcinoma cell lines are refractory toward TRAIL treatment (7-10). Thus, novel treatment strategies to improve TRAIL therapy for the dismal prognosis of this disease are in great demand.Oncolytic viruses...