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Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy
BACKGROUND: Diffuse pleural mesothelioma (DPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10652639/ https://www.ncbi.nlm.nih.gov/pubmed/37974213 http://dx.doi.org/10.1186/s13046-023-02889-6 |
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author | Singh, Anand Pruett, Nathanael Dixit, Shivani Gara, Sudheer K. Wang, Haitao Pahwa, Roma Schrump, David S. Hoang, Chuong D. |
author_facet | Singh, Anand Pruett, Nathanael Dixit, Shivani Gara, Sudheer K. Wang, Haitao Pahwa, Roma Schrump, David S. Hoang, Chuong D. |
author_sort | Singh, Anand |
collection | PubMed |
description | BACKGROUND: Diffuse pleural mesothelioma (DPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear factor-κB (NF-κB) and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair. METHODS: We used DPM cell lines, murine models (xeno- and allo-grafts), plus DPM patient samples to characterize anti-tumor effects of CBL0137 and to delineate specific molecular mechanisms. RESULTS: We verified that CBL0137 induced cell cycle arrest and apoptosis. We also discovered that DPM is a FACT-dependent cancer with overexpression of both subunits structure-specific recognition protein 1 (SSRP1), a poor prognosis indicator, and suppressor of Ty 16 (SUPT16H). We defined several novel uses of CBL0137 in DPM therapy. In combination with cisplatin, CBL0137 exhibited additive anti-tumor activity compared to monotherapy. Similarly, CBL0137 (systemic) could be combined with other novel agents like microRNA-215 (intrapleural) as a more effective regimen. Importantly, we established that CBL0137 induces immunogenic cell death that contributes to activating immune response pathways in DPM. Therefore, when CBL0137 is combined with dual immune checkpoint inhibitors DPM tumor growth is significantly suppressed. CONCLUSIONS: We identified an unrecognized molecular vulnerability of DPM based on FACT dependency. CBL0137 alone and in several combinations with different therapeutics showed promising efficacy, including that of improved anti-tumor immunity. Overall, these preclinical findings suggest that CBL0137 could be ideally suited for use in DPM clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02889-6. |
format | Online Article Text |
id | pubmed-10652639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106526392023-11-16 Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy Singh, Anand Pruett, Nathanael Dixit, Shivani Gara, Sudheer K. Wang, Haitao Pahwa, Roma Schrump, David S. Hoang, Chuong D. J Exp Clin Cancer Res Research BACKGROUND: Diffuse pleural mesothelioma (DPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear factor-κB (NF-κB) and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair. METHODS: We used DPM cell lines, murine models (xeno- and allo-grafts), plus DPM patient samples to characterize anti-tumor effects of CBL0137 and to delineate specific molecular mechanisms. RESULTS: We verified that CBL0137 induced cell cycle arrest and apoptosis. We also discovered that DPM is a FACT-dependent cancer with overexpression of both subunits structure-specific recognition protein 1 (SSRP1), a poor prognosis indicator, and suppressor of Ty 16 (SUPT16H). We defined several novel uses of CBL0137 in DPM therapy. In combination with cisplatin, CBL0137 exhibited additive anti-tumor activity compared to monotherapy. Similarly, CBL0137 (systemic) could be combined with other novel agents like microRNA-215 (intrapleural) as a more effective regimen. Importantly, we established that CBL0137 induces immunogenic cell death that contributes to activating immune response pathways in DPM. Therefore, when CBL0137 is combined with dual immune checkpoint inhibitors DPM tumor growth is significantly suppressed. CONCLUSIONS: We identified an unrecognized molecular vulnerability of DPM based on FACT dependency. CBL0137 alone and in several combinations with different therapeutics showed promising efficacy, including that of improved anti-tumor immunity. Overall, these preclinical findings suggest that CBL0137 could be ideally suited for use in DPM clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-023-02889-6. BioMed Central 2023-11-16 /pmc/articles/PMC10652639/ /pubmed/37974213 http://dx.doi.org/10.1186/s13046-023-02889-6 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Singh, Anand Pruett, Nathanael Dixit, Shivani Gara, Sudheer K. Wang, Haitao Pahwa, Roma Schrump, David S. Hoang, Chuong D. Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy |
title | Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy |
title_full | Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy |
title_fullStr | Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy |
title_full_unstemmed | Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy |
title_short | Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy |
title_sort | targeting facilitates chromatin transcription complex inhibits pleural mesothelioma and enhances immunotherapy |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10652639/ https://www.ncbi.nlm.nih.gov/pubmed/37974213 http://dx.doi.org/10.1186/s13046-023-02889-6 |
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