The ability of tumors to metastasize accounts for greater than 90% of all cancer-related mortalities. Metastasis is a multistep process, requiring the interplay between a cohort of tumor and host factors that allow for individual tumor cells to proliferate, invade, induce angiogenesis, escape immune surveillance, and ultimately survive and grow within secondary tissues. While this multistep process is thought to require many genetic and epigenetic events that provide selective advantages to metastatic cells, it is still unclear which changes are required late in tumor progression and in the metastatic pathway. Therefore, it is critical to develop new technologies to determine the contribution of individual cancer-related genes to metastatic progression. Our hypothesis is that multiple genes/proteins will need to be targeted to ultimately prevent and/or treat metastasis, and that RNA interference (RNAi) in the context of a specific replication-competent retroviral vector-based delivery system can be used to determine optimal therapeutic targets and strategies for the future. Our laboratory has developed a replication-competent retroviral delivery system to induce RNAi, with the purpose of validating multiple metastatic target genes, and with the intention of developing novel therapeutic strategies to prevent and/or treat metastatic disease. Our laboratory has previously identified a number of gene targets that appear to be essential for metastatic progression in two ras-mediated models: murine fibrosarcoma, and human pancreatic cancer. Using our replication-competent retroviral vector-based delivery system, we have disrupted expression of these target genes in vitro, by disrupting each gene individually as well as all genes in combination. Furthermore, we are in the process of utilizing these two independent models to analyze the effect of individual and combinational target gene disruption on tumor growth and metastatic progression in vivo. These studies will likely identify the optimal gene therapeutic/pharmacological strategies that are needed to effectively treat metastatic disease.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]