Bystander effect contributes to the antitumor efficacy of CaSm antisense gene therapy in a preclinical model of advanced pancreatic cancer.

Pancreatic adenocarcinoma (PC) is an aggressive malignancy resistant to standard treatment modalities. Previously, we have reported that cancer-associated Sm-like protein (CaSm) contributes to the neoplastic transformation of PC. In this study, we utilized a recently established preclinical model of PC to determine if molecular targeting of CaSm can serve as the basis for a novel PC therapy. In a subcutaneous tumor model, intratumoral administration of an adenoviral vector encoding CaSm antisense RNA (Ad-alphaCaSm) significantly inhibited Panc02 tumor growth. Furthermore, in a metastatic tumor model, systemic administration of Ad-alphaCaSm resulted in a significant decrease in the number of hepatic metastases and increased survival time. We assessed the efficiency of in vivo delivery and observed significant levels of vector transduction in tissues containing PC, as well as a bystander effect that was amplifying the efficacy of CaSm gene therapy. This bystander effect was also active in vitro and was shown to be at least partially independent of host-related mechanisms. We conclude that CaSm antisense gene therapy is an effective novel therapy for PC and that the antitumor efficacy is dependent on both direct and bystander mechanisms.

Establishing a murine pancreatic cancer CaSm model: up-regulation of CaSm is required for the transformed phenotype of murine pancreatic adenocarcinoma.

We have recently shown that the cancer-associated Sm-like protein (CaSm) is overexpressed in human pancreatic adenocarcinoma (PC). However, the role of CaSm in the process of neoplastic transformation remains unclear. To define further the role of CaSm in PC transformation, we have established a murine model based on the murine pancreatic cancer cell lines Panc02 and Panc03. CaSm is overexpressed in the aggressive Panc02 cells and expressed at much lower levels in the more indolent Panc03 cells. Up-regulation of CaSm in Panc03 cells increased in vitro proliferation and anchorage-independent growth and promoted subcutaneous tumor establishment and growth in syngeneic mice. Conversely, adenoviral down-regulation of CaSm in Panc02 led to significant inhibition of cellular proliferation and anchorage-independent growth in vitro and complete abolition of tumor growth and metastasis in vivo. Up-regulation of CaSm in NIH3T3 resulted in loss of contact inhibition and increased soft agar colony formation in vitro. The requirement for CaSm overexpression for neoplastic transformation confirms the concept that CaSm is a critical oncogene and potential target for molecular intervention. Furthermore, establishment of the murine clinically relevant model of pancreatic metastases provides a framework for the generation of preclinical data to support the development of novel molecular therapies targeting CaSm.