The immune system limits the development and progression of many cancers, including breast cancer. Indeed, patients with advanced breast cancer sometimes may also suffer from immunological disorders, at higher rates than other cancers. Most of these so-called ¿paraneoplastic diseases¿ are related to autoimmune problems, reflecting a disorientation of normal immunity in cancer patients. Since cancers evolve ways to elude the immune system, there is significant interest in stimulating or `reprogramming¿ the immune system to help patients fight their disease. One of the chief attractions of recruiting the immune system is that it can `dodge and weave¿ with disease cells as they evolve. This is a major attraction, insofar as the advanced stages of breast cancer are characterized by diverse and plastic cells that ultimately lead to mortality. We propose to test whether small molecule inhibitors of the immunosuppressive enzyme IDO can be used to attack breast cancer. This project stems from our recent discovery of a possible link between IDO and Bin1, a cancer suppressor gene identified in our laboratory. Preliminary work indicates that IDO elevation may be one consequence of the frequent loss of Bin1 observed in breast tumors. Notably, others have shown that IDO suppresses immune responses, specifically those associated with T cell activation. Thus, tumors where IDO is elevated may escape recognition and destruction by the immune system. We wish to test this hypothesis by determining whether small molecule drugs that inhibit IDO can promote tumor recognition and rejection. One bioactive inhibitor molecule for these tests is already in hand; we will characterize others we identified recently by `drug screening¿ activities. To test the action of these agents, we will use a well-established mouse model for breast cancer (the MMTV-neu `oncomouse¿). In this model, mammary carcinomas arise spontaneously due to the presence of a mutated form of the HER-2 gene, which is commonly activated in human breast cancer. This proposal for an IDEA Award offers several appealing and innovative elements. First, the project is a `translational¿ project to develop basic research observations toward clinical applications. The Bin1- IDO connection offers an opportunity for new insights into the pathology of breast cancer. It may also help guide IDO development in the most logical manner. This project will probe the role of immunity in breast cancer in a new way, and it will establish IDO as a target for breast cancer drug discovery. Second, while IDO has been reported to suppress the immune system, and to be elevated in cancer, the role of IDO in promoting breast cancer has not been explored. Third, while there is great interest in strategies to recruit the immune system in cancer patients, few drug-based strategies have been identified. Our proposal addresses this deficit. Drug-based strategies to promote tumor immunity offer advantages over biological or genetic strategies to achieve this end (e.g., gene therapy, antibodies, cytokines, cell-based therapies, etc.). Drug molecules disperse throughout the body, so they can readily attack disseminated, metastatic disease. Biological agents can be problematic in this regard because their access to diseased cells is not always uniform or efficient. The development of small molecule drugs is easier, because it takes advantage of established pharmacological and clinical principles to optimize drug delivery, dispersion, persistence, etc. Fourth, IDO has biochemical properties that make it highly tractable to drug development. This is important: the most pathologically interesting molecules in cancer cells are often poorly tractable to therapeutic development. Lastly, the Principal Investigator of this project has expertise and experience in drug discovery gained in the pharmaceutical industry, supporting the proposed exploration of IDO inhibitors as potential cancer drugs. In summary, this project offers an opportunity to perform `proof-of-concept¿ experiments to establish IDO as a focus for breast cancer drug development.