Pancreatic cancer is an extremely aggressive neoplasm whose incidence equals its death rate. Despite extensive analysis, no effective therapeutic approaches for diminishing the morbidity associated with this disease are available. By appropriate pharmacological manipulation, human melanoma cells can be induced to lose tumorigenic potential, irreversibly growth arrest and terminally differentiate. Through the use of subtraction hybridization, a novel gene associated with these changes in human melanoma cells, melanoma differentiation associated gene-7 (mda-7), has been identified. Ectopic expression of mda-7 using a recombinant adenovirus, Ad.mda-7, promotes growth suppression and apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb or p53 + Rb. Moreover, growth and progression of human breast, lung and cervical cancer cells in vivo in nude mice are inhibited by Ad.mda-7. In contrast, no deleterious effect is apparent following Ad.mda-7 infection of normal human cells. Selective induction of apoptosis in multiple tumor cell types correlates with an elevation in the level of the pro-apoptotic protein BAX and an increase in the ratio of BAX to BCL-2. In contrast to its apoptosis-inducing effects in the majority of human cancers, pancreatic carcinomas are refractory to Ad.mda-7. However, when Ad.mda-7 is combined with approaches that specifically inhibit expression of the K-ras oncogene, which is mutated in approximately 85 to approximately 95 percent of pancreatic carcinomas, a loss of viability by induction of apoptosis results. These intriguing observations suggest that a combinatorial approach consisting of a cancer-specific apoptosis-inducing gene and an oncogene inactivation strategy may provide the basis for developing an effective molecular-target based therapy for pancreatic cancer. Experiments will expand on these observations and determine the mechanism underlying the synergy and develop potential cancer therapeutic viruses, including Ads expressing a combination of mda-7 and antisense K-ras and an Ad displaying cancer-restricted replication and cytolytic activity in the context of pancreatic carcinoma cells. The present studies will provide the obligatory preclinical support for novel approaches with significant potential for rapid translation into rational methods for treating patients' afflicted with an invariably incurable disease, pancreatic cancer.
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