Reexpression of Human Somatostatin Receptor Gene 2 Gene Mediated by Oncolytic Adenovirus Increases Antitumor Activity of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand against Pancreatic Cancer

Abstract

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...

Synergistic antitumor effect of TRAIL and IL-24 with complete eradication of hepatoma in the CTGVT-DG strategy

“…Furthermore, CTGVT-DG strategy has much better antitumor effect than that of CTGVT with single gene, on account of compensative or synergistic effect of two genes. We have more than six papers reporting essentially complete elimination of xenograft tumor of different tissues [6][7][8][32][33][34], among which the best one is the combined use of ZD55-TRAIL and ZD55-IL-24. There are two contributions of this paper: (i) the combination application of ZD55-TRAIL and ZD55-IL-24 showed good antitumor effect for several xenograft tumors, such as liver, gaster, lung, breast, and prostate carcinoma; (ii) the mutual up-regulating antitumor effect displaying that TRAIL could be induced by expression of ZD55-TRAIL [ Fig.…”

A Novel E1B-55kD-Deleted Oncolytic Adenovirus Carrying Mutant KRAS-Regulated hdm2 Transgene Exerts Specific Antitumor Efficacy on Colorectal Cancer Cells

“…Besides, although AdKRhdm2 holds promise as an anticancer agent, previous clinical experiences have shown that E1B-55kD-deleted adenoviruses alone were in most cases not potent enough to generate adequate responses. Strategies to augment therapeutic efficacies, including using combination therapies with CRAds and chemotherapeutic agents (4)(5)(6)(7)22), and incorporating therapeutic genes as members of transgenes into CRAd vectors, could be considered (34,35).…”

Anticancer Gene Transfer for Cancer Gene Therapy

“…TRAIL oncolytic gene therapy utilized the chimeric Adenovirus AD5/35 which is able to transduce cancer cells without the use of a receptor, replicate in cancer cells and allow TRAIL expression which lead to apoptosis induction (Chen et al, 2009). Efficacy of this vector was shown in leukemia, gastric cancer and pancreatic cancer in vivo (Zhang et al, 2009b, Jin et al, 2009. TRAIL has been extensively analyzed in a previous chapter of this book since it is one of the "anticancer genes" which are able to promote tumor-specific apoptosis initiation when overexpressed without being toxic in normal cells.…”