It has been clear from our past work and that of others, those elevations in one specific type of glycosylation, fucosylation, is associated with HCC. Indeed this modification is the basis of the only biomarker approved by the food and drug administration for the detection of HCC, AFP-L3. However, in several studies, the specificity of fucosylation for cancer detection has been questioned. That is, many people with cirrhosis, and without cancer, have been shown to have elevations in fucose as well. The nature of this change is the objective of our parent grant and this revision application. The fucosylation of N-linked glycoproteins is observed in two major forms- alpha-1, 6 linked core fucosylation and outer-arm fucosylation (alpha 1, 2, 3 or 4 linked). We have recently shown that the elevations in the cirrhotic, non-HCC patients are attributable to elevations in alpha-1, 3 linked outer arm fucosylation and not alpha-1, 6 core fucosylation. While these are distinct glycan modifications, most fucose-binding lectins cannot differentiate these subtle differences. As a result, assays using commercial fucose-binding lectins suffer from poor specificity. Hence, we have recently made novel fucose binding lectins with enhanced specificity towards the core fucose modification that is more specific for cancer. Therefore, in this revision application for parent grant R01 CA120206, we will use these novel reagents and findings to support a collaborative cancer imaging study to not only detect cancer at the earliest stages possible but to reduce over diagnosis.
In specific aim 1, we will determine the ability of the core fucosylated proteins to increase the specificity of imaging as part of ACRIN protocol 6690. The main objective of this trial is to compare the accuracy of radiologic staging of HCC by CT and MRI and to determine if biomarkers can be used to increase the specificity of these imaging techniques. The presence of HCC in this case will be determined by explant pathology of participants who undergo liver transplantation for treatment of their liver disease.
In aim 2, we will determine if another glycan modification, increased branching, can be used in combination with MRI and CT-Scan for the specific detection of HCC. At the end of this supplement we will have extended the aims of the parent application and shown that specific changes in glycosylation can be used to assist imaging to specifically identify those patients with HCC.

Public Health Relevance

This research project will help develop a noninvasive method for the early detection of liver cancer. Liver cancer rates have doubled in the last 10 years and are continuing to rise. Unfortunately, the 5 year survival rates are only 8%, primarily due to late diagnosis. As is the case with breast cancer and cervical cancer, early detection will be vital to reduce the morbidity associated with this cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01CA120206-08S1
Application #
8699560
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rinaudo, Jo Ann S
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Mehta, Anand; Comunale, Mary Ann; Rawat, Siddhartha et al. (2016) Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation. Sci Rep 6:27965
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Thio, Chloe L; Smeaton, Laura; Hollabaugh, Kimberly et al. (2015) Comparison of HBV-active HAART regimens in an HIV-HBV multinational cohort: outcomes through 144 weeks. AIDS 29:1173-82
Mehta, Anand; Herrera, Harmin; Block, Timothy (2015) Glycosylation and liver cancer. Adv Cancer Res 126:257-79
Zhao, Xuesen; Guo, Fang; Comunale, Mary Ann et al. (2015) Inhibition of endoplasmic reticulum-resident glucosidases impairs severe acute respiratory syndrome coronavirus and human coronavirus NL63 spike protein-mediated entry by altering the glycan processing of angiotensin I-converting enzyme 2. Antimicrob Agents Chemother 59:206-16
Powers, Thomas W; Neely, Benjamin A; Shao, Yuan et al. (2014) MALDI imaging mass spectrometry profiling of N-glycans in formalin-fixed paraffin embedded clinical tissue blocks and tissue microarrays. PLoS One 9:e106255

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