This proposal is submitted as an exploratory research center grant in response to the PA (PAR-03-046) """"""""DEVELOPMENTAL CENTERS FOR RESEARCH ON COMPLEMENTARY AND ALTERNATIVE MEDICINE (DCRC)"""""""" It meets PA objectives by 1) developing basic, translational, and clinical research to explore the feasibility and scientific rationale for use of mushroom extracts as immunopotentiating agents; b) facilitating the development of the capacity of investigators at Bastyr University to participate in basic and translational CAM research; 3) enhancing the capacity of investigators at the University of Minnesota to participate in translational and clinical CAM research. Mushroom extracts contain a number of bioactive substances that can induce the immune system. We hypothesize that by combining the mutual expertise of our two institutions, we can determine if beta-glucans in Tv represent the major constituent group that upregulates the immune system to cause tumor regression and amelioration of treatment side effects and synergizes with other immunomodulatory compounds in the complex mushroom preparation to induce more potent antitumor immune responses than isolated beta-glucan fractions alone. To test this hypothesis, we have assembled a group of projects that will address the following specific aims. In Project 1, we will use a murine cancer model to: 1) determine optimal dose and schedule of Tv extracts to invoke an immune response; 2) assess the effect of non-glucan constituents on the biodistribution and activity of fluorescently-labeled beta-glucan purified from our Tv extracts; 3) determine the necessity of an intact immune response for Tv beta-glucans efficacy. In Project 2, we will perform an in vitro/ex vivo human trial to 1) determine the capacity of a complex Tv preparation to modulate antitumor immune responses in healthy human subjects; 2) determine the role of the beta-glucan/CR3 pathway in antitumor immune responses induced by the complex Tv extract; and 3) assess the importance of synergy in immunomodulatory activities of the complex Tv preparation. In Project 3, we will perform a Phase I/II dose escalation trial to determine the ability of complex Tv extracts to provoke an immune response in patients with localized breast cancer and to acquire the necessary data to conduct a future randomized clinical trial. These projects will be supported by two cores: Clinical and Bioanalytical. In our second goal, the DCRC will use the resources of the University of Minnesota to provide Bastyr personnel with training experiences needed to enhance their capability to compete for funding. Finally, the DCRC work to use the resources at Bastyr University is to promote the clinical and cultural perspectives needed at the University of Minnesota to carry out CAM research. We expect that this data will lead to a greater understanding of the mechanisms of Tv-enhance immunopotentiation, the creation of phase II clinical trials, and application for further NIH funding in the future.
