Glypican-1 Is a Novel Target for Stroma and Tumor Cell Dual-Targeting Antibody-Drug Conjugates in Pancreatic Cancer
Shigehiro Tsujii1,2, Satoshi Serada3,4, Minoru Fujimoto2,5
1Department of Surgery, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
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.
Insights
Targeting glypican-1 (GPC1) with GPC1-ADC(MMAE) effectively inhibits pancreatic cancer growth by targeting cancer-associated fibroblasts. This novel antibody-drug conjugate shows promise for stroma-rich tumors like PDAC.
Area of Science:
- Oncology
- Cancer Biology
- Drug Development
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma, rich in cancer-associated fibroblasts (CAFs), which hinders chemotherapy efficacy.
- Glypican-1 (GPC1) is overexpressed in PDAC and linked to poorer patient survival, with notable expression on CAFs.
- CAFs contribute to the tumor microenvironment, impeding drug delivery and treatment response in PDAC patients.
Purpose of the Study:
- To evaluate the preclinical antitumor activity of a novel GPC1 antibody-drug conjugate, GPC1-ADC(MMAE), in PDAC.
- To investigate the potential of GPC1 as a therapeutic target in PDAC, particularly within the tumor stroma.
- To assess the efficacy of GPC1-ADC(MMAE) in targeting both GPC1-positive CAFs and cancer cells.
Main Methods:
- Generation of GPC1-ADC(MMAE) by conjugating a GPC1 antibody with monomethyl auristatin E.
- In vitro assessment of GPC1-ADC(MMAE) on GPC1-positive PDAC cell lines.
- In vivo evaluation using patient-derived tumor xenograft (PDX) models of PDAC, including stroma-positive/cancer-negative models.
Main Results:
- GPC1-ADC(MMAE) demonstrated significant inhibition of GPC1-positive PDAC cell lines in vitro.
- Potent antitumor effects were observed in PDAC PDX models, targeting both CAFs and heterogeneous cancer cells.
- The conjugate showed efficacy in stroma-rich PDAC PDX models, with MMAE released from CAFs inducing apoptosis in neighboring cancer cells and inhibiting tumor growth.
Conclusions:
- GPC1 is a promising therapeutic target for PDAC and other solid tumors with GPC1-positive stroma.
- Targeting GPC1 on CAFs using GPC1-ADC(MMAE) represents a viable therapeutic strategy for stroma-rich cancers like PDAC.
- GPC1-ADC(MMAE) exhibits unique and potent antitumor activity, suggesting its potential clinical application in PDAC treatment.
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