A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma

Munekage, Eri; Serada, Satoshi; Tsujii, Shigehiro; Yokota, Keiichiro; Kiuchi, Keita; Tominaga, Kenji; Fujimoto, Minoru; Kanda, Mizuki; Uemura, Sunao; Namikawa, Tsutomu; Nomura, Taisei; Murakami, Ichiro; Hanazaki, Kazuhiro; Naka, Tetsuji

doi:10.1016/j.neo.2021.07.006

Cited by 14 publications

(18 citation statements)

References 31 publications

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“…In this case, the specificity of an mAb is coupled with the toxicities of an anti-cancer drug to focus the activity of the drug at the tumor site. In this direction, two interesting preclinical studies were performed in PDAC and ESCC in-vitro and in-vivo models using an anti-GPC1 conjugated with monomethyl auristatin F and monomethyl auristatin E, respectively [ 98 , 108 ]. Both of the ADCs showed promising activity in-vitro and in the in-vivo models [ 98 , 108 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this direction, two interesting preclinical studies were performed in PDAC and ESCC in-vitro and in-vivo models using an anti-GPC1 conjugated with monomethyl auristatin F and monomethyl auristatin E, respectively [ 98 , 108 ]. Both of the ADCs showed promising activity in-vitro and in the in-vivo models [ 98 , 108 ]. These results provide encouraging evidence for the set-up of an ADC recognizing GPC1 to be transferred to the clinical management of PDAC patients and others with GPC1-expressing tumors.…”

Section: Discussionmentioning

confidence: 99%

“…An antibody-drug conjugate (ADC) is a novel class of pharmacological compounds that take advantage of the specificity of an mAb to focus the toxicity of the anti-cancer drug at the tumor site [ 98 ]. The pioneer of ADC was the scientist Paul Ehrlich, who almost 100 years ago suggested the possibility of creating an antibody–toxin complex to improve toxin specificity [ 99 ].…”

Section: Targeting Strategiesmentioning

confidence: 99%

“…The ADC demonstrated anti-tumor activity in both the xenograft models and in the PDX, even if the anti-tumor activity is higher in the xenograft murine model, the levels of GPC1 being more homogeneous in comparison with the PDX model [ 108 ]. In 2021, Munekage and colleagues designated a novel ADC based on a humanized anti-GPC1 mAb bound to the monomethyl auristatin E (MMAE) [ 98 ]. This study reinforces the data from Nishigaki, showing a higher in-vitro antitumor activity of the ADC in GPC1-positive cell lines compared to those GPC1-negative [ 98 ].…”

Section: Targeting Strategiesmentioning

confidence: 99%

“…In 2021, Munekage and colleagues designated a novel ADC based on a humanized anti-GPC1 mAb bound to the monomethyl auristatin E (MMAE) [ 98 ]. This study reinforces the data from Nishigaki, showing a higher in-vitro antitumor activity of the ADC in GPC1-positive cell lines compared to those GPC1-negative [ 98 ]. The ADC also demonstrated high anti-tumor activity in the in-vivo xenograft models, in PDX murine models of PDAC, and in esophageal squamous cell carcinoma (ESCC) [ 98 ].…”

Section: Targeting Strategiesmentioning

confidence: 99%

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

Busato

Mossenta

et al. 2022

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers, with a 5-year survival rate of 7% and 80% of patients diagnosed with advanced or metastatic malignancies. Despite recent advances in diagnostic testing, surgical techniques, and systemic therapies, there remain limited options for the effective treatment of PDAC. There is an urgent need to develop targeted therapies that are able to differentiate between cancerous and non-cancerous cells to reduce side effects and better inhibit tumor growth. Antibody-targeted strategies are a potentially effective option for introducing innovative therapies. Antibody-based immunotherapies and antibody-conjugated nanoparticle-based targeted therapies with antibodies targeting specific tumor-associated antigens (TAA) can be proposed. In this context, 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 achieved by a specific antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy. In this review, we describe the main clinical features of PDAC. We propose the proteoglycan GPC1 as a useful TAA for PDAC-targeted therapies. We also provide a digression on the main developed approaches of antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy, which can be used to target GPC1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Targeting Strategiesmentioning

confidence: 99%

Section: Targeting Strategiesmentioning

confidence: 99%

Section: Targeting Strategiesmentioning

confidence: 99%

See 3 more Smart Citations

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

Busato

Mossenta

et al. 2022

IJMS

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Extracellular glypican‐1 affects tumor progression and prognosis in esophageal cancer

Shibata,

Konishi,

Arita

et al. 2024

Cancer Medicine

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IntroductionCells are covered with a glycan surface layer that is referred to as the glycocalyx (GCX). It has been reported that the formation of the GCX is promoted on cancer cells and is associated with tumor growth and metastasis. Heparan sulfate proteoglycan glypican‐1 (GPC1) is a core protein of the GCX that is overexpressed in esophageal squamous cell carcinoma (ESCC) and is involved in the development and progression of cancer cells. The purpose of the present study is to analyze the utility of GPC1 as a new biomarker ralated to glycocalyx that reflects therapeutic effect and prognosis of ESCC.MethodsWe measured the concentration of GPC1 protein in preoperative plasma from advanced esophageal cancer patients and examined its relationships with clinicopathological factors and therapeutic efficacy, and the effects of extracellular GPC1 were investigated.ResultsThe following clinical factors were significantly correlated with the preoperative high GPC1 concentration: male, tumor size ≥30 mm, venous invasion, pT factor ≥2, pStage ≥3, residual tumor, and distant metastatic recurrence. Both overall and recurrence‐free survival were significantly worse in the high GPC1 group. Extracellular GPC1 protein concentration reflected intracellular GPC1 expression. Furthermore, we examined the effects of extracellular recombinant human (rh)GPC1 on ESCC cells, and found that extracellular rhGPC1 affects cell motility, including migration and invasion.ConclusionsThese results demonstrated the utility of extracellular GPC1 as a biomarker, which can be assayed from a less invasive blood sample‐based liquid biopsy. Extracellular GPC1 protein plays a role in both tumor cell motility and cancer progression. Thus, plasma GPC1 is a useful biomarker for esophageal cancer progression and may be a potential candidate of therapeutic target.

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Integrating TCGA and single-cell sequencing data for colorectal cancer: a 10-gene prognostic risk assessment model

Lu,

Li,

Yuan

et al. 2023

Discov Onc

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Colorectal cancer represents a significant health threat, yet a standardized method for early clinical assessment and prognosis remains elusive. This study sought to address this gap by using the Seurat package to analyze a single-cell sequencing dataset (GSE178318) of colorectal cancer, thereby identifying distinctive marker genes characterizing various cell subpopulations. Through CIBERSORT analysis of colorectal cancer data within The Cancer Genome Atlas (TCGA) database, significant differences existed in both cell subpopulations and prognostic values. Employing WGCNA, we pinpointed modules exhibiting strong correlations with these subpopulations, subsequently utilizing the survival package coxph to isolate genes within these modules. Further stratification of TCGA dataset based on these selected genes brought to light notable variations between subtypes. The prognostic relevance of these differentially expressed genes was rigorously assessed through survival analysis, with LASSO regression employed for modeling prognostic factors. Our resulting model, anchored by a 10-gene signature originating from these differentially expressed genes and LASSO regression, proved adept at accurately predicting clinical prognoses, even when tested against external datasets. Specifically, natural killer cells from the C7 subpopulation were found to bear significant associations with colorectal cancer survival and prognosis, as observed within the TCGA database. These findings underscore the promise of an integrated 10-gene signature prognostic risk assessment model, harmonizing single-cell sequencing insights with TCGA data, for effectively estimating the risk associated with colorectal cancer.

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A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma

Cited by 14 publications

References 31 publications

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

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

Extracellular glypican‐1 affects tumor progression and prognosis in esophageal cancer

Integrating TCGA and single-cell sequencing data for colorectal cancer: a 10-gene prognostic risk assessment model

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