The hypothesis of the original grant was that fucosylation increases with the development of hepatocellular carcinoma (HCC) and that fucosylated glycoprotein(s) will make sensitive and specific markers of HCC. This hypothesis has been confirmed and in our analysis of over 1000 patient samples, we have clearly shown that fucosylated glycoproteins can make sensitive and specific markers of HCC, either alone or in combination with other markers. However, in our analysis, we have determined that in addition to core fucosylation there are many other changes that occur with liver disease. Some of these changes are cancer specific and can be used to complement our existing markers, while others can occur with just liver disease (inflammation) and lead to false positives. Thus in aim 1, we will develop novel and unique reagents that will dramatically improve our assays and continue our discovery efforts to find biomarkers that can be used clinically for the management of HCC.
In aim 2 we will utilize our new lectins and continue our discovery efforts in an effort to find new biomarkers in biomarker negative populations that can complement our existing markers and lead to 100% sensitivity and 100% specificity. Finally in aim 3, we will test our lead markers in a NCI sponsored study comprising of over 350 cases of HCC and which we pre-qualified for. At the end of this 5 year period we will have validated our biomarkers and definitively proved our hypothesis that fucosylated proteins can make sensitive and specific markers of HC.

Public Health Relevance

This research project will help develop a non invasive 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 is vital to reduce the morbidity associated with this cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120206-07
Application #
8402835
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Rinaudo, Jo Ann S
Project Start
2006-04-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
7
Fiscal Year
2013
Total Cost
$311,949
Indirect Cost
$91,499
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Betesh, Lucy; Comunale, Mary Ann; Wang, Mengjun et al. (2017) Identification of fucosylated Fetuin-A as a potential biomarker for cholangiocarcinoma. Proteomics Clin Appl 11:
Wang, Mengjun; Sanda, Miloslav; Comunale, Mary Ann et al. (2017) Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC. Cancer Epidemiol Biomarkers Prev 26:795-803
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
Wang, Mengjun; Devarajan, Karthik; Singal, Amit G et al. (2016) The Doylestown Algorithm: A Test to Improve the Performance of AFP in the Detection of Hepatocellular Carcinoma. Cancer Prev Res (Phila) 9:172-9
Wang, Mengjun; Comunale, Mary Ann; Herrera, Harmin et al. (2016) Identification of IgM as a contaminant in lectin-FLISA assays for HCC detection. Biochem Biophys Res Commun 476:140-5
Holst, Stephanie; Heijs, Bram; de Haan, Noortje et al. (2016) Linkage-Specific in Situ Sialic Acid Derivatization for N-Glycan Mass Spectrometry Imaging of Formalin-Fixed Paraffin-Embedded Tissues. Anal Chem 88:5904-13
Norton, Pamela; Comunale, Mary Ann; Herrera, Harmin et al. (2016) Development and application of a novel recombinant Aleuria aurantia lectin with enhanced core fucose binding for identification of glycoprotein biomarkers of hepatocellular carcinoma. Proteomics 16:3126-3136
Heijs, Bram; Holst, Stephanie; Briaire-de Bruijn, Inge H et al. (2016) Multimodal Mass Spectrometry Imaging of N-Glycans and Proteins from the Same Tissue Section. Anal Chem 88:7745-53
Meibalan, Elamaran; Comunale, Mary Ann; Lopez, Ana M et al. (2015) Host erythrocyte environment influences the localization of exported protein 2, an essential component of the Plasmodium translocon. Eukaryot Cell 14:371-84
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

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