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Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance
SIMPLE SUMMARY: This study reports a potential new drug—Cerebraca wafer—that is designed to deliver its active pharmaceutical ingredient, (Z)-n-butylidenephthalide (BP), directly into the surgical cavity created when a brain tumor is resected. The therapeutic mechanism of Cerebraca wafer was shown t...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870243/ https://www.ncbi.nlm.nih.gov/pubmed/35205800 http://dx.doi.org/10.3390/cancers14041051 |
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author | Liu, Ching-Ann Liu, Wei-Hsiu Ma, Hsin-I Chen, Yuan-Hao Hueng, Dueng-Yuan Tsai, Wen-Chiuan Lin, Shinn-Zong Harn, Horng-Jyh Chiou, Tzyy-Wen Liu, Jen-Wei Lee, Jui-Hao Chiu, Tsung-Lang |
author_facet | Liu, Ching-Ann Liu, Wei-Hsiu Ma, Hsin-I Chen, Yuan-Hao Hueng, Dueng-Yuan Tsai, Wen-Chiuan Lin, Shinn-Zong Harn, Horng-Jyh Chiou, Tzyy-Wen Liu, Jen-Wei Lee, Jui-Hao Chiu, Tsung-Lang |
author_sort | Liu, Ching-Ann |
collection | PubMed |
description | SIMPLE SUMMARY: This study reports a potential new drug—Cerebraca wafer—that is designed to deliver its active pharmaceutical ingredient, (Z)-n-butylidenephthalide (BP), directly into the surgical cavity created when a brain tumor is resected. The therapeutic mechanism of Cerebraca wafer was shown to involve the following: (1) an IC(50) of BP against tumor stem cells four times lower than that of bis-chloroethylnitrosourea (BCNU); (2) a synergistic effect between BP and temozolomide (TMZ), as demonstrated by a reduction in O(6)-methylguanine-DNA-methyltransferase (MGMT) expression level; (3) BP inhibition of programmed cell death-ligand 1 (PD-L1) protein levels, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The implantation of Cerebraca wafer is safe, no drug-related adverse events (AEs) and serious AEs (SAEs) were found. The median overall survival (OS) of patients receiving high-dose Cerebraca wafer have exceeded 17.4 months, and a 100% progression-free survival (PFS) rate at six month was achieved. In sum, these findings demonstrate that the Cerebraca wafer has superior therapeutic effects to Gliadel wafer in recurrent high-grade gliomas. ABSTRACT: In recurrent glioblastoma, Gliadel wafer implantation after surgery has been shown to result in incomplete chemical removal of residual tumor and development of brain edema. Furthermore, temozolomide (TMZ) resistance caused by O(6)-methylguanine-DNA-methyltransferase (MGMT) activation and programmed cell death-ligand 1 (PD-L1) expression leads to immune-cold lesions that result in poorer prognosis. Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), is designed to eliminate residual tumor after glioma resection. An open-label, one-arm study with four dose cohorts, involving a traditional 3 + 3 dose escalation clinical trial, of the Cerebraca wafer combined with TMZ on patients with recurrent high-grade glioma, was conducted. Of the 12 patients who receive implantation of Cerebraca wafer, there were no drug-related adverse events (AEs) or serious AEs (SAEs). The median overall survival (OS) of patients receiving low-dose Cerebraca wafer was 12 months in the group with >25% wafer coverage of the resected tumor, which is longer than OS duration in previously published studies (Gliadel wafer, 6.4 months). Patients who received high-dose Cerebraca wafer treatment had not yet died at the data cut-off date; a 100% progression-free survival (PFS) rate at six month was achieved, indicating the median OS of cohort IV was more than 17.4 months. In vitro study of the primary cells collected from the patients revealed that the IC(50) of BP against tumor stem cells was four times lower than that of bis-chloroethylnitrosourea (BCNU). A synergistic effect between BP and TMZ was demonstrated by a reduction in MGMT expression. Furthermore, BP inhibited PD-L1 expression, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The better therapeutic effect of Cerebraca wafer on recurrent high-grade glioma could occur through re-sensitization of TMZ and reduction of PD-L1. |
format | Online Article Text |
id | pubmed-8870243 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88702432022-02-25 Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance Liu, Ching-Ann Liu, Wei-Hsiu Ma, Hsin-I Chen, Yuan-Hao Hueng, Dueng-Yuan Tsai, Wen-Chiuan Lin, Shinn-Zong Harn, Horng-Jyh Chiou, Tzyy-Wen Liu, Jen-Wei Lee, Jui-Hao Chiu, Tsung-Lang Cancers (Basel) Article SIMPLE SUMMARY: This study reports a potential new drug—Cerebraca wafer—that is designed to deliver its active pharmaceutical ingredient, (Z)-n-butylidenephthalide (BP), directly into the surgical cavity created when a brain tumor is resected. The therapeutic mechanism of Cerebraca wafer was shown to involve the following: (1) an IC(50) of BP against tumor stem cells four times lower than that of bis-chloroethylnitrosourea (BCNU); (2) a synergistic effect between BP and temozolomide (TMZ), as demonstrated by a reduction in O(6)-methylguanine-DNA-methyltransferase (MGMT) expression level; (3) BP inhibition of programmed cell death-ligand 1 (PD-L1) protein levels, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The implantation of Cerebraca wafer is safe, no drug-related adverse events (AEs) and serious AEs (SAEs) were found. The median overall survival (OS) of patients receiving high-dose Cerebraca wafer have exceeded 17.4 months, and a 100% progression-free survival (PFS) rate at six month was achieved. In sum, these findings demonstrate that the Cerebraca wafer has superior therapeutic effects to Gliadel wafer in recurrent high-grade gliomas. ABSTRACT: In recurrent glioblastoma, Gliadel wafer implantation after surgery has been shown to result in incomplete chemical removal of residual tumor and development of brain edema. Furthermore, temozolomide (TMZ) resistance caused by O(6)-methylguanine-DNA-methyltransferase (MGMT) activation and programmed cell death-ligand 1 (PD-L1) expression leads to immune-cold lesions that result in poorer prognosis. Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), is designed to eliminate residual tumor after glioma resection. An open-label, one-arm study with four dose cohorts, involving a traditional 3 + 3 dose escalation clinical trial, of the Cerebraca wafer combined with TMZ on patients with recurrent high-grade glioma, was conducted. Of the 12 patients who receive implantation of Cerebraca wafer, there were no drug-related adverse events (AEs) or serious AEs (SAEs). The median overall survival (OS) of patients receiving low-dose Cerebraca wafer was 12 months in the group with >25% wafer coverage of the resected tumor, which is longer than OS duration in previously published studies (Gliadel wafer, 6.4 months). Patients who received high-dose Cerebraca wafer treatment had not yet died at the data cut-off date; a 100% progression-free survival (PFS) rate at six month was achieved, indicating the median OS of cohort IV was more than 17.4 months. In vitro study of the primary cells collected from the patients revealed that the IC(50) of BP against tumor stem cells was four times lower than that of bis-chloroethylnitrosourea (BCNU). A synergistic effect between BP and TMZ was demonstrated by a reduction in MGMT expression. Furthermore, BP inhibited PD-L1 expression, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The better therapeutic effect of Cerebraca wafer on recurrent high-grade glioma could occur through re-sensitization of TMZ and reduction of PD-L1. MDPI 2022-02-18 /pmc/articles/PMC8870243/ /pubmed/35205800 http://dx.doi.org/10.3390/cancers14041051 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Liu, Ching-Ann Liu, Wei-Hsiu Ma, Hsin-I Chen, Yuan-Hao Hueng, Dueng-Yuan Tsai, Wen-Chiuan Lin, Shinn-Zong Harn, Horng-Jyh Chiou, Tzyy-Wen Liu, Jen-Wei Lee, Jui-Hao Chiu, Tsung-Lang Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance |
title | Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance |
title_full | Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance |
title_fullStr | Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance |
title_full_unstemmed | Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance |
title_short | Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance |
title_sort | interstitial control-released polymer carrying a targeting small-molecule drug reduces pd-l1 and mgmt expression in recurrent high-grade gliomas with tmz resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870243/ https://www.ncbi.nlm.nih.gov/pubmed/35205800 http://dx.doi.org/10.3390/cancers14041051 |
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