Conventional therapies, including surgery coupled with chemotherapy, have not resulted in significant improvements in overall survival rates for ovarian cancer. In this context, novel therapeutic modalities are required for this disease. Gene therapy represents a rational and potentially effective approach for ovarian carcinoma. To this end, a number of distinct cancer gene therapy approaches have been developed for ovarian carcinomas, which are predicated upon direct gene delivery to tumor cells. To achieve effective gene delivery, recombinant adenoviral vectors have been employed based on their superior in vivo efficacy characteristics. Whereas adenoviral vectors are understood to exhibit superior levels of in vivo gene transfer compared to available alternative vector systems, present levels may nonetheless be sub optimal for ovarian cancer gene therapy applications. On this basis, we have endeavored to modify the tropism of adenoviral vectors to achieve enhanced gene delivery to tumor cells as a means to improve the overall feasibility of these cancer gene therapy strategies. We have achieved adenovirus retargeting using genetic strategies to alter tropism. In the present proposal, we seek to further develop these approaches to allow the development of adenoviral vectors, which allow maximal enhancement of gene delivery to ovarian cancer cells. With this objective in mind, we have developed a highly novel strategy of Ad tropism alteration whereby multiple, and distinct, retargeting ligands are genetically incorporated into the viral capsid """"""""complex mosaic"""""""". The ability to achieve biological access to multiple cellular entry pathways potentially allows for maximized gene delivery to tumor cells deficient in the primary Ad receptor. We hypothesize that these """"""""complex mosaic"""""""" adenoviral vectors will allow the achievement of an improved therapeutic index in the context of mda-7/IL-24 based gene therapy approaches for ovarian carcinoma. In principle, these """"""""complex mosaic"""""""" adenoviral vectors should also prove beneficial for treatingother cancers, including prostate cancer (Project 1: Fisher) and malignant glioma (Project 2: Dent). This strategy may also be amenable to increase the infectivity of adenoviral vectrs in which replication is restricted to cancer cells by the progression elevated gene-3 promoter and mda-7/IL-24 is expressed in a different region of the adenoviral genome (proposed in Project 1:Fisher). This vector would provide a direct means of enforcing replication in cancer cells resulting in their cytolysis with concomitant production of mda-7/IL-24. Such a """"""""complex mosaic"""""""" adenoviral vector would offer profound cancer specific activity, not only in ovarian, but also in other cancers and be of direct relevance to the theme of this program project, to increase the translational aspects of mda- 7/IL-24 for cancer therapy.
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