This Program Project Grant involves investigators from the University of Southern California participating in a multi disciplinary and highly interactive research effort on the development of gene therapy approaches for the treatment of cancer. The investigators are drawn from both basic science and clinical departments. Similarly, the projects reflect a central theme of using the basic disciplines of molecular biology, molecular genetics, cell biology and human genetics to bridge the gaps in our knowledge and use cellular transduction for clinical treatment. The Program consists of five research Projects and three Core resources. In Project l Dr. Parkman and colleagues will use retroviral vectors to mark positively selected hematopoietic stem cells in order to follow patients with Acute Lymphocytic Leukemia and to transduce such cells with the human multiple drug resistance gene for delivery to patients undergoing autologous bone marrow transplantation. In Project 2, Dr. Kedes and colleagues will develop transcriptionally active DNA vectors to genetically engineer and implant rodent myoblasts in order to deliver, both locally and systemically, a variety of antineoplastic polypeptides in animal tumor models. In Project 3 Dr. Donald Kohn and colleagues will define the role of DNA methylation in vector silencing and the ability of novel vectors to achieve persistent expression. In Project 4, Dr. Gunther Dennert and colleagues will test the ability of the glucose regulated protein gene promoter to drive the expression of cytokines in tumors in order to asses the role of these proteins in stimulating cell mediated immunity to transplanted tumors. In Project 5, Dr. W. French Anderson and colleagues will design chimeric retroviral envelope proteins to replace the natural coat proteins in an attempt to develop cell-type specific gene therapy delivery vehicles. The three Core resources include administration, viral vector development and animal models and these are integrated and interdependent. Finally, the Program is integrated in the University research community and in particular with the USC Gene Therapy Program which is a partnership between the Norris Comprehensive Cancer Center/Institute for Genetic Medicine Joint Gene Therapy Program and the Gene Therapy Programs of the Childrens Hospital Los Angeles.
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