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Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts

SIMPLE SUMMARY: GC1118 is a novel anti-EGFR monoclonal antibody with a distinct mode of epitope binding. Its therapeutic efficacy has been validated in preclinical studies of several cancers. We evaluated the anti-tumor efficacy of GC1118 against glioblastoma (GBM) using patient-derived xenografts (...

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Autores principales: Lee, Kyoungmin, Koo, Harim, Kim, Yejin, Kim, Donggeon, Son, Eunju, Yang, Heekyoung, Lim, Yangmi, Hur, Minkyu, Lee, Hye Won, Choi, Seung Won, Nam, Do-Hyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693807/
https://www.ncbi.nlm.nih.gov/pubmed/33142709
http://dx.doi.org/10.3390/cancers12113210
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author Lee, Kyoungmin
Koo, Harim
Kim, Yejin
Kim, Donggeon
Son, Eunju
Yang, Heekyoung
Lim, Yangmi
Hur, Minkyu
Lee, Hye Won
Choi, Seung Won
Nam, Do-Hyun
author_facet Lee, Kyoungmin
Koo, Harim
Kim, Yejin
Kim, Donggeon
Son, Eunju
Yang, Heekyoung
Lim, Yangmi
Hur, Minkyu
Lee, Hye Won
Choi, Seung Won
Nam, Do-Hyun
author_sort Lee, Kyoungmin
collection PubMed
description SIMPLE SUMMARY: GC1118 is a novel anti-EGFR monoclonal antibody with a distinct mode of epitope binding. Its therapeutic efficacy has been validated in preclinical studies of several cancers. We evaluated the anti-tumor efficacy of GC1118 against glioblastoma (GBM) using patient-derived xenografts (PDXs). GC1118 exhibited anti-tumor efficacy comparable to that of cetuximab in a subset of PDXs, and EGFR amplification was a potential biomarker for predicting its therapeutic efficacy. Growth inhibitory and direct apoptotic effects on GBM tumor cells were confirmed in in vitro analyses. In intracranial PDXs, GC1118 significantly improved survival outcome, indicating its potential to cross the blood–brain barrier. These results support the clinical potential of GC1118 in treating GBM, further prompting the requirement of a clinical trial. ABSTRACT: We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood–brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies.
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spelling pubmed-76938072020-11-28 Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts Lee, Kyoungmin Koo, Harim Kim, Yejin Kim, Donggeon Son, Eunju Yang, Heekyoung Lim, Yangmi Hur, Minkyu Lee, Hye Won Choi, Seung Won Nam, Do-Hyun Cancers (Basel) Article SIMPLE SUMMARY: GC1118 is a novel anti-EGFR monoclonal antibody with a distinct mode of epitope binding. Its therapeutic efficacy has been validated in preclinical studies of several cancers. We evaluated the anti-tumor efficacy of GC1118 against glioblastoma (GBM) using patient-derived xenografts (PDXs). GC1118 exhibited anti-tumor efficacy comparable to that of cetuximab in a subset of PDXs, and EGFR amplification was a potential biomarker for predicting its therapeutic efficacy. Growth inhibitory and direct apoptotic effects on GBM tumor cells were confirmed in in vitro analyses. In intracranial PDXs, GC1118 significantly improved survival outcome, indicating its potential to cross the blood–brain barrier. These results support the clinical potential of GC1118 in treating GBM, further prompting the requirement of a clinical trial. ABSTRACT: We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood–brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies. MDPI 2020-10-31 /pmc/articles/PMC7693807/ /pubmed/33142709 http://dx.doi.org/10.3390/cancers12113210 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Kyoungmin
Koo, Harim
Kim, Yejin
Kim, Donggeon
Son, Eunju
Yang, Heekyoung
Lim, Yangmi
Hur, Minkyu
Lee, Hye Won
Choi, Seung Won
Nam, Do-Hyun
Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
title Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
title_full Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
title_fullStr Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
title_full_unstemmed Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
title_short Therapeutic Efficacy of GC1118, a Novel Anti-EGFR Antibody, against Glioblastoma with High EGFR Amplification in Patient-Derived Xenografts
title_sort therapeutic efficacy of gc1118, a novel anti-egfr antibody, against glioblastoma with high egfr amplification in patient-derived xenografts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693807/
https://www.ncbi.nlm.nih.gov/pubmed/33142709
http://dx.doi.org/10.3390/cancers12113210
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