We propose here a Program Project to study the mechanisms of tumor suppression by the human retinoblastoma (RB) gene. The RB gene is the prototype cancer suppressor gene wherein tumors occur only in the absence of the normal suppressor gene product. We recently have shown that reintroduction of the normal RB gene via a retroviral vector can suppress the neoplastic phenotype in RB deficient retinoblastoma and osteosarcoma tumor cell lines. We now propose a broad collaborative effort by many specialized laboratories to focus on cancer suppression with the RB gene. Five separate laboratory groups will be integrated into a unit to accelerate the progress in this field. Our strategy will be to model tumor suppression at the biochemical, cellular and organism level. The specific lines of investigation will be divided into 5 units: 1) identification of RB mutations in different tumor types with reintroduction of the RB gene for tumor suppression; 2) characterization of the second RB transcript to study this new gene within the RB gene; 3) construction of improved vectors for delivery of the normal RB gene into tumor cells; 4) elucidation of the biochemical and cellular functions of the RB protein; and 5) generation of chimeric and transgenic mice to model hereditary cancer and subsequent gene therapy. In support to these units will be three cores: 1) Pathology and Nude mice; 2) Antibodies and Oligonucleotides; and 3) Administration. The investigators who are to participate in the Program Project have specialized expertise over the full spectrum of molecular, cellular, and organism biology and will now focus this talent on cancer suppression by the RB gene. This proposal puts forth a cohesive, interrelated, and interdependent series of studies designed to model tumor suppression and cancer suppressor gene therapy. These studies will serve as the basic research foundation for consideration of gene therapy in human cancer.
