Our long-term goal is to develop an adenovirus (Ad)-based therapy for invasive cervical carcinoma (ICC). Over the past 5 years, we have generated and tested a series of oncolytic Ad vectors that possess modified capsids for tumor targeting and utilize a new concept to achieve tumor-specific gene expression and replication. In animal models, we have demonstrated that these vectors are non-toxic and eliminate metastases derived from human tumor cell lines after systemic vector application. The goal of this proposal is to further increase the clinical utility of our oncolytic vector. i) Ad transduction, replication, and oncolysis will be studied on a representative number (N>65) of primary invasive cervical cancer (ICC) cultures that we will obtain through collaborations with hospitals in Seattle and Dakar, Senegal. ii) Our vectors will be based on serotype B adenoviruses that have the potential to efficiently and specifically infect malignant tumor cells and that have low serum prevalence in humans. iii) We will employ new principles to achieve tumor-specific viral replication and to express pro-apoptotic gene products from Ad vectors. iv) DNA microarrays will be used to identify cellular pathways/factors the affect Ad replication and oncolysis, to construct a panel of genes that predicts which cancer patients would benefit from therapy with oncolytic vectors, and to arm our oncolytic vector with genes that enhance viral replication and lysis. ? ?
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