Glypican-3 is an oncofetal antigen that belongs to the glypican family of glycosyl-phosphatidylinositol-anchored heparin sulfate proteoglycans. Glypicans regulate the activity of several growth factors including Wnts, Hedgehogs, bone morphogenic proteins and fibroblast growth factors (FGFs) (Filmus et al. FEBS J. 2013, 280:2471-2476). Glypicans are characterized by a covalent linkage to complex polysaccharide chains called heparinsulphate glycosaminoglycans. Glypicans are involved in cell signaling at the cellular-extracellular matrix interface. (Sasisekharan et al., Nature ReviewslCancer, Volume 2 (2002). To date, six distinct members of the human glypican family have been identified. Cell membrane-bound glypican-3 is composed of two subunits, linked by one or more disulfide bonds.
Glypican-3 is expressed in fetal liver and placenta during development and is down-regulated or silenced in normal adult tissues. Mutations and depletions in the glypican-3 gene are responsible for the Simpson-Golabi-Behmel or Simpson dysmorphia syndrome in humans. Glypican-3 is expressed in various cancers and, in particular, hepatocellular carcinoma (“HCC”), melanoma, Wilm's tumor, and hepatoblastoma. (Jakubovic and Jothy; Ex. Mol. Path. 82:184-189 (2007); Nakatsura and Nishimura, Biodrugs 19(2):71-77 (2005). The cell surface form of Glypican-3 is highly expressed in HCC (>50%) and in other cancers including squamous lung cancer (approximately 25%).
Glypican-3 promotes tumor growth in vitro and in vivo by stimulating canonical Wnt signaling which induces the cytosolic accumulation and nuclear translocation of the transcription factor β-catenin (Filmus, supra). It has been shown that GPC3 can form a complex with several Wnts (Capurro et al., Cancer Res., 2005, 65:6245-6254), and Frizzleds, the signaling receptor for Wnts (Filmus, et al., Genome Biol., 2008, 9:224).
HCC is the third leading cause of cancer-related deaths worldwide. Each year, HCC accounts for about 1 million deaths. (Nakatsura and Nishimura, Biodrugs 19(2):71-77 (2005).) Hepatitis B virus, hepatitis C virus, and chronic heavy alcohol use leading to cirrhosis of the liver remain the most common causes of HCC. Its incidence has increased dramatically in the United States because of the spread of hepatitis C virus infection and is expected to increase for the next 2 decades. HCC is treated primarily by liver transplantation or tumor resection. Patient prognosis is dependent on both the underlying liver function and the stage at which the tumor is diagnosed. (Parikh and Hyman, Am J. Med. 120(3):194-202 (2007).) Effective HCC treatment strategies are needed.