Overall survival among patients affected with pancreatic carcinoma has remained essentially static despite the availability of contemporary surgery and chemotherapy modalities. This fact has argued strongly for the development of novel therapeutic approaches for pancreatic cancers. In this field, conditionally replicative adenoviruses (CRAds) agents offer a novel and potent modality to approach cancer of the pancreas. However, pancreatic cancer cells are especially resistant to infection by adenovirus, thus limiting the capability of CRAd agents to achieve effective lateralization within the tumor. In addition, the absence of promoter elements that demonstrate selective inducibility in pancreatic cancer cells has hampered the construction of CRAd agents with desired replicating specificity, the key to the achievement of acceptable therapeutic index. In this proposal, we construct enhanced CRAds to overcome these CRAd limitations. In the first instance, we have developed methods to alter the tropism of the adenovirus, thereby achieving infectivity enhancement for tumor cells. These maneuvers have dramatically improved the infectious potency of adenovirus onto pancreatic cancer tumor targets. As well, we have identified and characterized two novel promoter elements, which exhibit selective activity in pancreatic tumor targets. Here, we have shown that the cyclooxygenase-2 (cox-2) and midkine (MK) promoters exhibit the """"""""tumor ON / liver OFF"""""""" expression profile, which is critical for their utility in an adenoviral context. These findings directly address the limits of those agents for their application for pancreatic cancers but also offer the potential to derive CRAd agents for this target disease. Based on those considerations, it is clear that the combination of infectivity enhancement and cox-2 and/or MK controlled replication will offer the derivation of a CRAd agent with characteristics predicting its utility for cancer of the pancreas. The utility of these vectors will be established from the toxicological and anti-tumor effect standpoints.
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