Present clinical gene therapy research in patients with cancer has centered on two principal areas: 1) marker studies to determine the cellular trafficking of tumor infiltrating lymphocytes (TIL) cells and the basis for leukemic relapse following bone marrow transplantation and 2) cytokine gene transduction to increase immunological responses in patients with melanoma. In order to have a major impact in the treatment of cancer patients, however, gene therapy has to be integrated into clinical protocols in the early stages of therapy and applied to a broader range of cancers. Overall the present proposal """"""""Cellular Transduction For Drug Delivery in Cancer"""""""" is an integrated program between three units of the University of Southern California School of Medicine: the Kenneth Norris Jr. Cancer Center, the Institute for Genetic Medicine and the Childrens Hospital Los Angeles. The integrated program consists of clinical, pre-clinical, and basic science research into the area of drug delivery utilizing gene therapy techniques. the proposal represents the establishment of a new, interactive, gene therapy program and entails the development of new approaches to the gene therapy of cancer. The central research focus of the proposal is the use of target cells with capacity for long term gene expression to deliver anti-cancer gene therapy. The studies center on two such potential cellular delivery systems: hematopoietic stem cells (HSC) and myoblasts. Pre-clinical and clinical studies (Project 1) are proposed using HSC transduced with a drug resistance gene (DRG). The engraftment of DRG transduced HSC would result in increasing the ability of patients with both hematological malignancies and solid tumors to tolerate higher doses of chemotherapy without marrow suppression. Pre-clinical studies with myoblasts (Project 2) transduced with anti-cancer polypeptide genes (somatostatin analogs) are proposed. Myoblasts constitutively producing anti-cancer polypeptides would be expected to be more efficacious and cheaper than the intermittent administration of the same polypeptide. Central to the use of gene therapy for the delivery of anti-cancer drugs is the long term expression of the transduced gene. Some studies with both HSC and myoblasts have exhibited the phenomenon of """"""""silencing"""""""" i.e. the decrease expression of the transduced gene with time. Basic research into the mechanisms of silencing are proposed (Project 3) including the possibility that the introduction of methylation resistant islands in the promoter regions of the transduced gene may inhibit silencing. Both Project 2 and Project 3 will also investigate the function and efficacy of novel promoters and enhancers for the maximal and sustained delivery of recombinant gene products. A vector and animal core is integral to each of the three projects. Retroviral vectors are pivotal to Projects 1 and 2 and are one of the major elements of Project 2. The murine gene transfer/bone marrow transplantation (BMT) studies are fundamental to examining vector silencing in hematopoietic stem cells (Project 3) and an important element for evaluating the effects of the MDR-1 gene on conferring drug resistance to hematopoietic stem cells (Project 1).
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