Studies from many years ago suggested that the cell surface sialic acid N-glycolylneuraminic Acid (NeuSGc) is an """"""""oncofetal antigen"""""""" in humans, and that patients with cancer express antibodies against it. Our application revisits this matter using modern glycomic and high-throughput approaches, and in the light of a new paradigm: that humans are genetically defective in synthesizing NeuSGc and can metabolically incorporate it into tumors from certain dietary sources (particularly red meat and milk). Furthermore, preliminary evidence indicates that the polyclonal human anti-Neu5Gc antibody response detects a wide and highly variable spectrum of NeuSGc-containing epitopes. We therefore propose to study total body burden of NeuSGc, NeuSGc-containing glycans on secreted glyconjugates and specific anti-NeuSGc-antibodies-as biomarkers for the early detection of carcinomas of the lung, pancreas and ovary. To achieve our goals, we have assembled an expert team of glycobiologists, chemists, oncologists and biostaticians, along with specialists on glycomics and on antibody-screening by microarrays. Using various established and newly developed approaches we propose to obtain baseline information on the nature and structural complexity of NeuSGc-glycan expression in primary human tumors, and in serum and urine samples from subjects with early and late-stage tumors. In parallel, we are developing a sensitive and specific method to determine the total body burden of NeuSGc. In order to define the antibody response, we will synthesize/obtain matched sets of glycans containing alpha-linked-NeuSGc or NeuSAc, and will validate and optimize a novel glycan array utilizing these targets. Glycan synthesis and conjugation will be optimized, array substrate and hybridization conditions determined, and inter-assay and inter-subject variability defined. The goal is to identify cancer-specific anti-NeuSGc antibody patterns by comparing cancer cases and controls. Initial approximations of sensitivity and specificity will be made at predefined interim analyses with decisions to expand or narrow testing of cancer types. The emerging data from this approach will be also used to define the need for additional iterations of the glycan array. Finally, we will use combinations of total body NeuSGc burden and/or specific NeuSGc-glycans and/or anti-NeuSGc antibody patterns, to identify cancer-specific differences between ill subjects with and without cancer, for use in early diagnosis and prognosis.
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