Research Project
6913982
DESCRIPTION (provided by applicant): Early diagnosis and immunotherapeutic stimulation of a patient's own immune system to detect and destroy tumors is the best hope for the treatment, prevention and eventual cure for ovarian cancer. The overall goal of this proposal is to conduct proof-of-concept studies to identify tumor-associated antigens (TAA) that will lead to the development of i) early stage diagnostics and ii) immunotherapeutics that induce strong cellular (T cell) and humoral (B cell) responses against ovarian tumors. The novelty of this program is in the identification of tumor-specific antigens that are both reactive to auto antibodies in the serum of ovarian cancer patients at progressive stages of disease and are also processed through the immune system Major Histocompatibility Complex (MHC) class I pathway and recognized by cytotoxic T lymphocytes. Discovery and preliminary evaluation of the antigens will begin in Project Phase I. The first Aim of this Phase I proposal is to conduct a comprehensive proteomic analysis to identify tumor-associated antigens reactive to serum immunoglobulin from primary ovarian cancer patients at different stages of disease, with the goal of identifying antigens common to the majority of patients sampled. This Aim will be achieved by immunoprecipitation of TAA from primary tumor lysates using patient serum as the source of autoantibodies and control serum to identify antigens found only in patient serum. The TAA will be fully characterized by mass spectroscopy and a TAA proteomics database will be generated. The second Aim is to identify the epitopes in these TAA that are recognized by the autoantibodies in cancer patient serum. Since native conformation and post-translational processing can have profound effects on antibody recognition, we will further characterize glycosylation patterns on these antigens and determine whether they play a role in antibody recognition. This emphasis on native proteins has important implications for our future work on the design of diagnostics and immunotherapeutics, as it takes into account the specificity of the interactions between native antigens and autoantibodies.
