Glypican-1 Is a Novel Target for Stroma and Tumor Cell Dual-Targeting Antibody–Drug Conjugates in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a stroma-rich cancer. Extracellular matrix proteins produced by cancer-associated fibroblasts (CAFs) found in tumor stroma that impedes effective delivery of chemotherapeutic agents results in poor response in patients with PDAC. Previously, our group reported that glypican-1 (GPC1) was overexpressed in human PDAC and negatively correlated with patient survival. Immunohistochemical analysis of 25 patients with PDAC tumor specimens revealed elevated expression of GPC1 in stromal cells and pancreatic cancer cells in 80% of patients. Interestingly, GPC1 was expressed on CAFs in PDAC. We generated a GPC1 antibody–drug conjugate conjugated with monomethyl auristatin E [GPC1-ADC(MMAE)] and evaluated its preclinical antitumor activity by targeting GPC1-positive CAF and cancer cells in PDAC. GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC cell lines in vitro. Furthermore, GPC1-ADC(MMAE) showed a potent antitumor effect in the PDAC patient-derived tumor xenograft (PDX) model against GPC1-positive CAF and heterogeneous GPC1-expressing cancer cells. Notably, GPC1-ADC(MMAE) showed robust preclinical efficacy against GPC1 in a stroma-positive/cancer-negative PDAC PDX model. GPC1-ADC(MMAE) was delivered and internalized to CAFs. Although apoptosis was not observed in CAFs, the released MMAE from CAFs via MDR-1 induced apoptosis of cancer cells neighboring CAFs and efficiently inhibited PDAC tumor growth. GPC1-ADC(MMAE) exhibited potent and unique antitumor activity in GPC1-positive PDAC PDX models, which suggests that GPC1 is a novel therapeutic target in PDAC and other stromal GPC1-positive solid tumors. These findings show that targeting GPC1 on CAF using GPC1-ADC(MMAE) is a useful approach in case of stroma-rich tumors such as PDAC.

The Proteoglycan Glypican-1 as a Possible Candidate for Innovative Targeted Therapeutic Strategies for Pancreatic Ductal Adenocarcinoma

“…In recent years, many agents have been used to realize this fundamental idea, and to date, several mAbs represent a valid therapeutic option for more cancer patients [ 17 ]. GPC1 appears to be a useful TAA for antibody-based therapies against PDAC because it is specifically overexpressed in PDAC tissues [ 18 , 19 ]. Considering the functions that the GPC1 protein performs in the context of the tumor cell and tumor microenvironment, the functional neutralization of GPC1 by a specific mAb would provide benefits for reducing tumor growth, metastasis, and angiogenesis, as well as remodeling the tumor microenvironment, making it more susceptible to treatments and reducing the state of immunosuppression [ 18 , 19 ].…”

“…Because GPC1 is exposed on the cell surface and overexpressed in PDAC tissues, whereas it is not expressed or is expressed at low levels in other healthy tissues, it embodies the properties of TAA, which mAbs can potentially target [ 18 , 19 ]. From a functional point of view, GPC1 can be considered as a potential target for mAbs because it can interact with various growth factors, such as fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), heparin-binding EGF-like growth factor, and TGF-β [ 19 ]. These growth factors are known to contribute to tumor cell proliferation, metastasis, and angiogenesis [ 19 ].…”

“…From a functional point of view, GPC1 can be considered as a potential target for mAbs because it can interact with various growth factors, such as fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), heparin-binding EGF-like growth factor, and TGF-β [ 19 ]. These growth factors are known to contribute to tumor cell proliferation, metastasis, and angiogenesis [ 19 ]. Moreover, in the context of PDAC, GPC1 expression has been detected in cancer-associated fibroblasts (CAF), which secrete the stroma.…”

“…Moreover, in the context of PDAC, GPC1 expression has been detected in cancer-associated fibroblasts (CAF), which secrete the stroma. The presence of the stroma makes the tumor microenvironment difficult to pass for a conventional therapeutic strategy and creates a state of immunosuppression that promotes tumor growth [ 19 ]. For these reasons, functional neutralization of GPC1 by specific mAbs could potentially provide benefits by interfering with tumor growth, metastasis, and angiogenesis, and remodeling the tumor microenvironment to be more responsive to treatment and reduce immunosuppression.…”

“…In particular, antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy can be proposed using antibodies targeting specific tumor-associated antigens (TAA). In this regard, glypican-1 (GPC1), which is highly expressed in PDAC and not expressed or expressed at very low levels in non-malignant lesions and healthy pancreatic tissues, is a useful TAA that can be targeted by specific antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy [ 18 , 19 ]. In this review, we describe the main clinical features of PDAC.…”