Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy.

Abstract

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.

• Authors: Anand Singh, Nathanael Pruett, Shivani Dixit, Sudheer K Gara, Haitao Wang, Roma Pahwa, David S Schrump, Chuong D Hoang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 42 Issue 1 Pg. 304 (Nov 16 2023) ISSN: 1756-9966 [Electronic] England
• PMID: 37974213 (Publication Type: Journal Article)
• Copyright: © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Chemical References

• Chromatin
• Cisplatin
• SSRP1 protein, human
• DNA-Binding Proteins
• High Mobility Group Proteins
• Transcriptional Elongation Factors
• SUPT16H protein, human
• Transcription Factors
• Cell Cycle Proteins
• MIRN215 microRNA, human
• MicroRNAs

Topics

• Humans
• Mice
• Animals
• Chromatin
• Cisplatin
• Mesothelioma, Malignant
• Mesothelioma (drug therapy, genetics)
• Immunotherapy
• DNA-Binding Proteins
• High Mobility Group Proteins
• Transcriptional Elongation Factors
• Transcription Factors
• Cell Cycle Proteins
• MicroRNAs (genetics)