Abstract 1315: Antibody-drug conjugate targeting glypican-1 inhibits tumor growth and tumor angiogenesis for glypican-1 positive cholangiocarcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-07, Vol.81 (13_Supplement), p.1315-1315
• Main Authors: Yokota, Keiichiro, Serada, Satoshi, Tsujii, Shigehiro, Murakami, Ichiro, Hanazaki, Kazuhiro, Naka, Tetsuji
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-1315

Cholangiocarcinoma (CCA) is one of highly malignant cancers. Systemic chemotherapy is used in many patients, however, there are few chemotherapy options, and their prognosis are poor. Therefore, it is necessary to develop new treatments. We have identified glypican-1 (GPC1) as a novel cancer antigen and reported that enhanced expression of GPC1 in esophageal squamous cell carcinoma and pancreatic cancer is significantly associated with poorer prognosis (Hara, Naka, et al. Br J Cancer. 2016, Nishigaki, Naka, et al. Br J Cancer. 2020). GPC1 is a heparan sulfate proteoglycan that is linked to the cell surface by a glycosylphosphatidylinositol anchor and promotes tumor growth, metastasis, and invasion by acting as a coreceptor, enhancing various signaling pathways. We recently identified that the expression of GPC1 was increased in cholangiocarcinoma. The present study aimed to develop a new therapy for cholangiocarcinoma using an antibody-drug conjugate (ADC) targeting glypican-1 (GPC1). Expression of GPC1 was evaluated in resected cholangiocarcinoma specimens and cell lines. GPC1 knockout cell was established from GPC1-positive cholangiocarcinoma cell line. The antitumor effect of monomethyl auristatin F conjugated GPC1-ADC was investigated in vitro and in vivo. GPC1 was highly expressed in cholangiocarcinoma cells and tissues. Immunohistochemical analysis of 49 extrahepatic cholangiocarcinoma patients revealed that 23 patients (47%) were high expression of GPC1, 24 patients (49%) were low expression of GPC1 and 2 patients (4%) were GPC1 negative. High-expression group demonstrated significantly poorer prognosis compared with the low-expression group in terms of disease-free survival and overall survival (p < 0.05). GPC1 was also expressed in tumor vessels of cholangiocarcinoma, but not on the vessels of nontumor tissues. Monomethyl auristatin F-conjugated GPC1-ADC significantly inhibited tumor growth against GPC1-positive cholangiocarcinoma cells in vitro and in vivo. In a GPC1 knockout xenograft model, GPC1-ADC partially inhibited tumor growth. Vascular endothelial cells in tumor tissues of GPC1-negative xenograft mice expressed GPC1 and were arrested in the G2/M phase of cell cycle by GPC1-ADC. In the present study, GPC1-ADC inhibits tumor growth and tumor angiogenesis for glypican-1 positive cholangiocarcinoma. Our preclinical data demonstrated GPC1-ADC as a promising strategy for GPC1-positive cholangiocarcinoma. Citation Format: Keiichiro Yokota, Satos