The major focus of the proposed project is the characterization and subsequent application of potential biomarkers of prevalent epithelial cancers in humans: the prostate cancer-specific carbohydrate antigen, F77, and for breast cancer, the more broadly-expressed epithelial cancer-associated carbohydrate antigen, AE3, both recognized by monoclonal antibodies. The project brings together a team of scientists with hugely complementary expertise and technical capabilities in carbohydrates, immunobiology, cancer cell biology, oncology, proteomics, and computational biology, as well as unique and well-annotated clinical specimens. We intend to adopt two main approaches to the structural characterization of F77 and AE3 antigens. The first is carbohydrate microarray analysis coupled with mass spectrometry using glycan arrays generated from the prostate cancer cell line, PC-3, and from AE3 antigen-positive epithelial mucins. The second is cell transfection of specific glycosyltransferases and other glyco-modifying enzymes such as sulfotransferases, an approach that has recently met with considerable success. Once characterized, the F77 and AE3 antigenic glycan sequences will be included as key probes in a carbohydrate microarray platform that we have established that presently includes more than 700 glycan sequences of glycoproteins and glycolipids. This will open the way to analysis of cancer patient sera for the presence of autoantibodies to F77 and AE3 and any other glycan biomarkers and to the design of new analysis procedures for the detection of aberrant glyco-antigenemia;one such approach will be by immune-proteomics. The expression of F77 and AE3 antigens will also be evaluated as tissue-based prognostic markers to identify aggressive primary prostate cancer. Finally, the mechanistic role of the F77 antigen in metastatic capabilities of cancer cells will be investigated to link the presence of the biomarker to the biology of the tumor. For prostate and breast cancers, existing screening methods for detection and characterization are variously unsatisfactory and unreliable. The application of biomarkers to detect prostate and breast cancer and to provide information about the prognosis of individual patients would be extremely useful and provide a very desirable alternatives to the current low sensitivity and/or specificity screening methods.

Public Health Relevance

This research aims to develop novel tissue- or serum-based biomarkers for breast and prostate cancer based on cancer-specific carbohydrate antigens. Characterization of the antigens will lead to antibody- or antigen-directed assays that can improve diagnosis and/or prognosis for these common cancers. This will improve screening strategies to better distinguish benign from malignant disease and decrease unnecessary biopsies or other interventions, and inform treatment decisions to diminish over-therapy of non-aggressive disease and enable earlier and more effective therapy of aggressive disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA168925-02
Application #
8539754
Study Section
Special Emphasis Panel (ZCA1-SRLB-4 (M1))
Program Officer
Kagan, Jacob
Project Start
2012-09-04
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$434,117
Indirect Cost
$123,725
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Lam, Lian; Czerniecki, Brian J; Fitzpatrick, Elizabeth et al. (2014) Interference-Free HER2 ECD as a Serum Biomarker in Breast Cancer. J Mol Biomark Diagn 4:151
Palma, Angelina S; Feizi, Ten; Childs, Robert A et al. (2014) The neoglycolipid (NGL)-based oligosaccharide microarray system poised to decipher the meta-glycome. Curr Opin Chem Biol 18:87-94
Nonaka, Motohiro; Fukuda, Michiko N; Gao, Chao et al. (2014) Determination of carbohydrate structure recognized by prostate-specific F77 monoclonal antibody through expression analysis of glycosyltransferase genes. J Biol Chem 289:16478-86
Zhang, Hongtao; Zhang, Shuang; Tao, Guanjun et al. (2013) Typing of blood-group antigens on neutral oligosaccharides by negative-ion electrospray ionization tandem mass spectrometry. Anal Chem 85:5940-9