Despite recent advances in the detection and treatment of most cancers, cancer related mortality has not decreased in the United States. In the near future, cancer is predicted to overtake heart disease as the number one cause of death. It is clear that new approaches are needed to treat these diseases. Cancer is the result of disruption of the pathways that regulate cell proliferation. These pathways include mitogenic signals, growth inhibitory signals, and cell survival signals. Preliminary evidence suggests that these latter signals differ between normal cells and cancer cells, as well as between cancers derived from solid tissue cells and hematopoietic cells. We postulate that better understanding these differences will allow the development of novel cancer therapies. The overall goals of this proposal are to understand the perturbations in the programmed cell death (PCD) pathway in cancer cells, and to determine whether the differences between cancer cells and normal cells can be exploited to develop new therapeutic agents. To accomplish these goals, adenovirus vectors will be used to specifically inactivate inhibitory components of the PCD pathway. Viruses that target three different points in the PCD pathway will be analyzed. These vectors, the bcl-x, adenovirus, the mbm-2 adenovirus, and the hrk adenovirus have several qualities that make them ideal agents that can be used to study both the biology and biochemistry of the PCD pathway and used as gene therapy agents. Cancers of Breast, Ovarian, Bladder and Hematopoietic origin will be analyzed. These cancers were chosen to explore differences in PCD pathways in these tumors, and because adenovirus vectors have therapeutic potential in these diseases. The projects in this proposal are integrated to achieve these goals. Project #1, Biochemistry and function of hrk, will examine the role of a new gene, hrk, in PCD in normal and cancer cells. An adenovirus vector that expresses hrk will be made and used by each project to determine the role of this gene in PCD in each respective type of cancer cell. Project #2, Targeting PCD in Breast and Ovarian cancer cells will utilize each of the adenovirus vectors for effects on normal and malignant breast cancer cells. Animal models to test the utility of these vectors are described. Clinical trials using the bcl-x/s adenovirus in high dose chemotherapy and autologous BMT in breast cancer and for treatment of ascites in patients with ovarian cancer are planned. Project #3, targeting PCD in Leukemia, will explore the regulation of PCD in normal and leukemic hematopoietic cells. Strategies to use adenovirus to specifically kill leukemia cells contaminating the bone marrow of cells used for autologous BMT will be tested. Project #4, Targeting PCD in bladder cancer, will determine the role of the bcl-2 family in bladder cancer. Clinical trials using the bcl-x/s adenovirus are envisioned.
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