CaSm antisense gene therapy: a novel approach for the treatment of pancreatic cancer.

Pancreatic adenocarcinoma is a major clinical problem with few effective treatment options. In the United States 29,000 cases are diagnosed annually with an associated mortality rate greater than 90%. Given this dismal prognosis, a better understanding of the molecular controls that govern pancreatic cancer is clearly needed in order to develop more effective therapies. As such, our group has been actively investigating the identification and potential application of novel gene targets for this disease. We have recently identified the cancer-associated Sm-like (CaSm) oncogene, shown that it is overexpressed in 87% of human pancreatic cancer samples, and clearly demonstrated that it functions as a classic oncogene. We have also been able to show that an adenovirus expressing antisense RNA to the CaSm gene (Ad-alpha CaSm) is able to reduce endogenous CaSm mRNA expression and decrease anchorage-independent growth. A single intratumor injection of Ad-alpha CaSm extended survival in an in vivo SCID mouse model of human pancreatic cancer. To gain insight into the mechanism of Ad-alpha CaSm's anti-tumor effect, cell cycle studies were performed. Ad-alpha CaSm treatment of pancreatic cancer cells resulted in a cytostatic block with decreased G1-phase and increased DNA content in vitro. Importantly, the combination of Ad-alpha CaSm with gemcitabine (an S-phase active chemotherapy) significantly extended survival time beyond either therapy alone. These studies have defined the CaSm oncogene as a novel gene target for therapy and have begun to define its potential role in the pathogenesis of pancreatic cancer.