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SRI International’s Tumor Glycome Laboratory Finds Carbohydrate Biomarkers to Target Breast Cancers
MENLO PARK, Calif.—October 21, 2015—The field of precision medicine acknowledges the wide variation among people and diseases. A group at SRI Biosciences, a division of SRI International, has taken another step in the direction of specific cancer diagnostics and therapy, showing for the first time that carbohydrate molecules that determine blood type can also be used to detect different forms of breast cancer, including some triple-negative breast cancer tumors.
While most scientists searching for cancer-detection biomarkers approach the problem primarily from the perspective of changes in genes (genomics) or proteins (proteomics), SRI’s Tumor Glycome Laboratory focuses on carbohydrate (glycomic) changes.
“Cancer is quite diverse, consisting of many different types, so if we can determine what type of cancer someone has, we can then treat it specifically. That’s the focus of precision medicine,” said Denong Wang, Ph.D., director of SRI’s Tumor Glycome Laboratory, which was established in 2008 as one of the member laboratories of the National Cancer Institute’s Alliance of Glycobiologists for Detection of Cancer. “Our contention is not only that there are genetic differences in cancer, but there are also glycomic differences for precision medicine to target.”
Previous research has shown that hallmarks of cancer include biochemical changes within cells that result in production of aberrant carbohydrate molecules (glycans). Such abnormal glycans may decorate the surface of tumor cells to form tumor biomarkers that are suitable for immune targeting. The extraordinary diversity of the tumor glycome has made identifying such markers challenging.
Wang’s team has pioneered exploration of carbohydrate-based biomarkers using carbohydrate microarray technologies. In results recently published online in the Volume 2015 edition of Journal of Immunology Research, Wang’s group identified a marker that is over-expressed on the surface of breast cancer cells, referred to as gpHAE3. Wang noted that it was interesting to the team that this target glycan is formed around the core of common blood group antigens. The glycan is normally hidden, but becomes exposed on the surface of breast cancer cells as the result of the malignant transformation of a normal cell to a cancer cell. These types of biomarkers are referred to as “cryptic.” Changes in surface glycans, especially cryptic glycans, can trigger an immune response that generates antibodies, which can remain in circulating blood for months or longer.
“Detection of antibodies in serum is technically much easier than detection of tumor antigens,” Wang said, noting that detection of tumor antibodies for diagnosis and monitoring treatment is a new area of tumor research and a focus of the SRI Tumor Glycome Laboratory.
With knowledge of the cryptic glycan target, the team screened seven human breast cancer cell lines. They found that the target was readily detected on the majority of these breast tumors, including two of the four triple-negative breast cancer tumors. Triple-negative breast cancer accounts for up to 20 percent of breast cancers. These tumors lack the three most common receptors (estrogen, progesterone and Her2/neu) that fuel most breast cancer growth, rendering these tumors unresponsive to drugs targeting these receptors.
“The potential of these types of cryptic glycans in detecting breast cancer and targeting it through immunotherapy warrants further investigation,” said Wang. His team hopes to extend the work to a study of breast cancer patients to examine whether the marker is significantly associated with metastatic breast cancer or circulating breast tumor cells, especially in patients with triple-negative cancer, since those cells do not have any known specific surface biomarkers.
The advantage of identifying surface markers, Wang said, is that once the targets are known, his team can design antibodies against those targets to create highly selective treatments. Such antibodies can be used in humans both for diagnosing cancer and for treating it specifically.
Other contributors to this work are: Jiaoti Huang, M.D., Ph.D., Professor of Pathology and Laboratory Medicine and of Urology at UCLA, and Wang’s former lab members Jin Tang, M.D., Anhui Medical University, Hefei, China and Shaoyi Liu, M.D., Weill Medical College of Cornell University in New York.
This work is supported in part by NIH grants U01CA128416 and R56AI108388 and by SRI International IR&D funds. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Carbohydrate microarray analysis of antiepiglycanin mAb HAE3. Seventy-six glycoproteins, glycoconjugates, and polysaccharides were spotted in triplicates in 1 to 2 dilutions to yield the customized microarrays for antibody screening. (A) Microarray detections were shown as the mean fluorescent intensities (MFIs) of each microspot with antigen-binding signal in red and background reading in blue. Each error bar is constructed using one standard deviation from the mean of triplicate detections. The labeled antigens include HCA (ID# 1 and ID# 2), a number of blood group precursors (29#–32#), and a microarray spotting marker (80#). (B) Images of a microarray stained with HAE3 (5 μg/mL). (C) Schematic of a blood group substance structure with the conserved O-glycan core highlighted.
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