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.
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.
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|West, Connor A; Wang, Mengjun; Herrera, Harmin et al. (2018) N-Linked Glycan Branching and Fucosylation Are Increased Directly in Hcc Tissue As Determined through in Situ Glycan Imaging. J Proteome Res 17:3454-3462|
|Mehta, Anand S; Lau, Daryl T-Y; Wang, Mengjun et al. (2018) Application of the Doylestown algorithm for the early detection of hepatocellular carcinoma. PLoS One 13:e0203149|
|Black, Alyson P; Mehta, Anand S (2018) The search for biomarkers of hepatocellular carcinoma and the impact on patient outcome. Curr Opin Pharmacol 41:74-78|
|Kaczor-Urbanowicz, Karolina El?bieta; Deutsch, Omer; Zaks, Batia et al. (2017) Identification of salivary protein biomarkers for orthodontically induced inflammatory root resorption. Proteomics Clin Appl 11:|
|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|
|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|
|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|
|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|
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