Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy

Our plain-English summary of Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy, by A. Singh, N. Pruett, S. Dixit, et al (Journal of Experimental & Clinical Cancer Research, 2023).

The study

• Authors: A. Singh, N. Pruett, S. Dixit, S.K. Gara, H. Wang, R. Pahwa, D.S. Schrump, C.D. Hoang
• Journal: Journal of Experimental & Clinical Cancer Research
• Published: 2023;42(1):304
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

In plain English

This laboratory study tested an experimental drug, CBL0137 (curaxin), against diffuse pleural mesothelioma (DPM). It used human and mouse mesothelioma cell lines, mice carrying implanted tumors, and stored patient tumor samples. It did not study asbestos exposure. The drug acts on a protein complex called FACT, which has two parts, SSRP1 and SUPT16H. In 50 DPM tumors compared with 31 unmatched normal pleuras, RNA (transcript) levels were 9.23-fold higher for SSRP1 and 19.16-fold higher for SUPT16H. In public data on 85 specimens, high SSRP1 was associated with poorer survival. In cells, CBL0137 caused cancer cell death and stopped cell division at one stage. In mice with tumors in the chest cavity (5 per group), median survival was 38 days with the drug versus 25 days with a control treatment. Tumor growth in mice was suppressed more when CBL0137 was combined with cisplatin, with an experimental microRNA (miR-215-5p), or with two immune checkpoint drugs than with either treatment alone. The authors concluded that their findings support testing CBL0137 in people. All results came from cells, mice and tissue samples, not treated patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: experiments in human and mouse mesothelioma cell lines, mouse tumor models (xenografts and allografts), plus gene-expression analysis of stored patient tumor samples and public TCGA data
• Who was studied: 50 surgical DPM tumors (46 epithelioid, three biphasic, one sarcomatoid) compared with 31 non-patient-matched benign pleuras; TCGA mesothelioma data on 85 specimens; human DPM cell lines (H2052, H2373, H2596, H2452, MSTO-211H, and patient-derived lines from Mesobank UK); a normal pleural mesothelial cell line (NP1); mouse DPM cell lines (AB1, AB22, AB12); immunodeficient NSG mice and immunocompetent BALB/cJ mice (5 to 8 per group). Work done at the National Cancer Institute, Bethesda, MD, USA
• Exposure: No asbestos exposure was studied. The exposures were drug treatments: CBL0137 (curaxin) alone and combined with cisplatin, with miR-215-5p delivered into the pleural cavity in a hydrogel, or with anti-PD-1 plus anti-CTLA-4 antibodies (dual immune checkpoint inhibitors)
• Main results:
  • In DPM tumor tissues compared with normal pleura, measured by quantitative real-time PCR, SSRP1 transcript abundance was 9.23-fold higher (p = 0.0026) and SUPT16H transcript abundance 19.16-fold higher (p = 0.0008)
  • In TCGA mesothelioma data (n = 85), high SSRP1 expression was associated with poor overall survival (p < 0.01)
  • In epithelioid and sarcomatoid DPM cells, the concentration of CBL0137 that halved cell survival (IC50) was 200 to 380 nM. In the normal mesothelial cell line NP1 it was 756 nM
  • In DPM cells, CBL0137 induced apoptosis (cell death) and G2-M cell cycle arrest compared with control
  • In mice with intrapleural H2373 tumors (n = 5 per group), CBL0137 inhibited tumor growth. Median overall survival was 38 days with CBL0137 versus 25 days with control (p < 0.05)
  • In mice with subcutaneous MB52 tumors, CBL0137 alone and cisplatin alone suppressed tumor growth compared with control (p < 0.01). The combination showed the most pronounced suppression over 4 weeks (p < 0.001). Group sizes were vehicle n = 8, CBL0137 n = 8, cisplatin n = 7 and combination n = 6
  • In mice with intrapleural MB52 tumors (n = 5 per group), CBL0137 plus intrapleural miR-215-5p gave the best median overall survival, 39 days
  • In the same intrapleural model, median overall survival was 37 days with miR-215-SFH alone, 36 days with CBL0137 alone, and 31 days with control
  • RNA sequencing of two CBL0137-treated cell lines found 532 differentially expressed genes common to both lines: 316 downregulated and 216 upregulated
  • CBL0137 increased three markers of immunogenic cell death in DPM cells compared with control: release of ATP, release of HMGB1, and calreticulin on the cell surface
  • In immunocompetent mice with AB1 tumors, CBL0137 alone and dual checkpoint inhibitors alone each suppressed tumor growth compared with vehicle or isotype controls (p < 0.01)
  • In the same mice, CBL0137 combined with dual checkpoint inhibitors was even more effective (p < 0.001). Group sizes were vehicle n = 6, isotypes n = 6, CBL0137 n = 8, dual ICI n = 7 and combination n = 8
• The authors' conclusion: The authors concluded that their findings support human testing of CBL0137, alone and in combinations, particularly with dual immune checkpoint inhibitor regimens, as a novel therapeutic option for DPM
• Limitations the authors state:
  • TCGA has no normal samples, so high versus low SSRP1 expression in the survival analysis was defined relative to the median within the DPM cohort
  • The authors did not explore every mechanism of CBL0137 action

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunotherapy, Apoptosis, Prognosis, Cisplatin, checkpoint inhibitors, Clinical Trial.

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