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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA128442-05
Application #
8127913
Study Section
Special Emphasis Panel (ZCA1-SRRB-4 (J1))
Program Officer
Krueger, Karl E
Project Start
2007-08-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$383,566
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lu, Qiaozhen; Padler-Karavani, Vered; Yu, Hai et al. (2012) LC-MS analysis of polyclonal human anti-Neu5Gc xeno-autoantibodies immunoglobulin G Subclass and partial sequence using multistep intravenous immunoglobulin affinity purification and multienzymatic digestion. Anal Chem 84:2761-8
Cao, Hongzhi; Chen, Xi (2012) General consideration on sialic acid chemistry. Methods Mol Biol 808:31-56
Padler-Karavani, Vered; Song, Xuezheng; Yu, Hai et al. (2012) Cross-comparison of protein recognition of sialic acid diversity on two novel sialoglycan microarrays. J Biol Chem 287:22593-608
Wang, Xiaoxia; Chow, Renee; Deng, Liwen et al. (2011) Expression of Siglec-11 by human and chimpanzee ovarian stromal cells, with uniquely human ligands: implications for human ovarian physiology and pathology. Glycobiology 21:1038-48
Ding, Li; Yu, Hai; Lau, Kam et al. (2011) Efficient chemoenzymatic synthesis of sialyl Tn-antigens and derivatives. Chem Commun (Camb) 47:8691-3
Mitra, Nivedita; Banda, Kalyan; Altheide, Tasha K et al. (2011) SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas. J Biol Chem 286:23003-11
Padler-Karavani, Vered; Varki, Ajit (2011) Potential impact of the non-human sialic acid N-glycolylneuraminic acid on transplant rejection risk. Xenotransplantation 18:1-5
Shengshu, Huang; Hai, Yu; Xi, Chen (2011) Chemoenzymatic synthesis of ?2-3-sialylated carbohydrate epitopes. Sci China Chem 54:117-128
Padler-Karavani, Vered; Hurtado-Ziola, Nancy; Pu, Minya et al. (2011) Human xeno-autoantibodies against a non-human sialic acid serve as novel serum biomarkers and immunotherapeutics in cancer. Cancer Res 71:3352-63
Lau, Kam; Yu, Hai; Thon, Vireak et al. (2011) Sequential two-step multienzyme synthesis of tumor-associated sialyl T-antigens and derivatives. Org Biomol Chem 9:2784-9

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