bims-mesote Biomed News
on Mesothelioma
Issue of 2023–11–19
ten papers selected by
Laura Mannarino, Humanitas Research
  1. Updates in Management of Malignant Pleural Mesothelioma.
  2. Salvage pleurectomy/decortication following immunotherapy for malignant pleural mesothelioma.
  3. Deciphering signaling pathway interplay via miRNAs in malignant pleural mesothelioma.
  4. A deep learning-based model (DeepMPM) to help predict survival in patients with malignant pleural mesothelioma.
  5. The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma.
  6. Treatment with tumor-treating fields (TTFields) suppresses intercellular tunneling nanotube formation in vitro and upregulates immuno-oncologic biomarkers in vivo in malignant mesothelioma.
  7. Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy.
  8. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis.
  9. Functional assay for assessment of pathogenicity of BAP1 variants.
  10. Tumor treating fields: narrative review of a promising treatment modality for cancer.
  1. Curr Treat Options Oncol. 2023 Nov 17.
    Updates in Management of Malignant Pleural Mesothelioma.
    Alexius John, Hazel O'Sullivan, Sanjay Popat.
       OPINION STATEMENT: Malignant pleural mesothelioma (MPM) is an aggressive asbestos-associated thoracic malignancy that is usually incurable. As demonstrated in the landmark MARS2 trial, surgical resection does not improve survival outcomes and its role in managing MPM is limited. Whilst platinum-pemetrexed chemotherapy in combination with bevacizumab was the standard first-line approach for unresectable disease, landmark phase 3 trials have now established the role of immune checkpoint inhibitors (CPIs) in the upfront management of unresectable disease: either nivolumab-ipilimumab or carboplatin-pemetrexed-pembrolizumab. Patient selection for optimal strategy remains an ongoing question. For relapsed disease novel genomic-based therapies targeting a range of aberrations including losses of the tumour suppressor genes BAP1, CDKN2A and NF2, are being evaluated. Nonetheless, the future of MPM therapeutics holds promise. Here we overview current treatment strategies in the management of MPM.
    Keywords:  Chemoimmunotherapy; Genomic driven therapy; Mesothelioma; Peri-operative therapy; Radiotherapy; Surgery
    DOI:  https://doi.org/10.1007/s11864-023-01148-2
  2. Interdiscip Cardiovasc Thorac Surg. 2023 Nov 15. pii: ivad173. [Epub ahead of print]
    Salvage pleurectomy/decortication following immunotherapy for malignant pleural mesothelioma.
    Masaru Takenaka, Koji Kuroda, Katsuma Yoshimatsu, Masataka Mori, Masatoshi Kanayama, Akihiro Taira, Taiji Kuwata, Fumihiro Tanaka.
      Salvage surgery following immunotherapy is a promising treatment option for advanced malignant tumour. However, only a few cases of salvage surgery for malignant pleural mesothelioma (MPM) have been reported. This retrospective study was conducted to assess the feasibility of salvage surgery following immunotherapy for initially unresectabele MPM. Among 61 patients who received pleurectomy/decortication (P/D) for MPM, 7 patients received salvage P/D after immunotherapy. Surgical indication of salvage P/D was conversion to resectability in 5 patients and local relapse in 2 patients, and macroscopic complete resection was achieved in all patients. Although salvage P/D was associated with longer operation time (median, 507 min), higher intraoperative blood loss (median, 2573 mL) and higher morbidity (≥ Grade 3, 29%), no patient died after surgery. Radiographic response to immunotherapy was well correlated with pathologic response, as all 4 patients with partial response showed significant pathologic response (viable cells, ≤ 50%). With the median postoperative follow-up duration of 9.0 months, all patients were alive mostly without tumour recurrence as local recurrence developed in one patient. To conclude, salvage P/D after immunotherapy may be a feasible treatment option for selected patients with advanced MPM, which should be validated in future multi-institutional studies. In addition, a long-term follow-up is essential to reveal clinical benefit achieved with salvage P/D following immunotherapy.
    Keywords:  Immunotherapy; Mesothelioma; Pleurecotomy/decortication; Salvage surgery
    DOI:  https://doi.org/10.1093/icvts/ivad173
  3. Pathol Res Pract. 2023 Nov 13. pii: S0344-0338(23)00648-9. [Epub ahead of print]252 154947
    Deciphering signaling pathway interplay via miRNAs in malignant pleural mesothelioma.
    Aya Salman, Sherif S Abdel Mageed, Doaa Fathi, Mahmoud A Elrebehy, Ahmed I Abulsoud, Shereen Saeid Elshaer, Emad Gamil Khidr, Tohada M Al-Noshokaty, Reem Khaled, Nehal I Rizk, Mohammed S Elballal, Ghadir A Sayed, Mai A Abd-Elmawla, Manar Mohammed El Tabaa, Osama A Mohammed, Alaa Ashraf, Ahmed A El-Husseiny, Heba M Midan, Walaa A El-Dakroury, Mustafa Ahmed Abdel-Reheim, Ahmed S Doghish.
      Malignant pleural mesothelioma (MPM) is a highly invasive form of lung cancer that adversely affects the pleural and other linings of the lungs. MPM is a very aggressive tumor that often has an advanced stage at diagnosis and a bad prognosis (between 7 and 12 months). When people who have been exposed to asbestos experience pleural effusion and pain that is not explained, MPM should be suspected. After being diagnosed, most MPM patients have a one- to four-year life expectancy. The life expectancy is approximately six months without treatment. Despite the plethora of current molecular investigations, a definitive universal molecular signature has yet to be discovered as the causative factor for the pathogenesis of MPM. MicroRNAs (miRNAs) are known to play a crucial role in the regulation of gene expression at the posttranscriptional level. The association between the expression of these short, non-coding RNAs and several neoplasms, including MPM, has been observed. Although the incidence of MPM is very low, there has been a significant increase in research focused on miRNAs in the past few years. In addition, miRNAs have been found to have a role in various regulatory signaling pathways associated with MPM, such as the Notch signaling network, Wnt/β-catenin, mutation of KRAS, JAK/STAT signaling circuit, protein kinase B (AKT), and Hedgehog signaling pathway. This study provides a comprehensive overview of the existing understanding of the roles of miRNAs in the underlying mechanisms of pathogenic symptoms in MPM, highlighting their potential as viable targets for therapeutic interventions.
    Keywords:  Malignant pleural mesothelioma; MiRNAs; Oncogene; Pathogenesis; Tumor Suppressor
    DOI:  https://doi.org/10.1016/j.prp.2023.154947
  4. Transl Cancer Res. 2023 Oct 31. 12(10): 2887-2897
    A deep learning-based model (DeepMPM) to help predict survival in patients with malignant pleural mesothelioma.
    Wei Li, Minghang Zhang, Siyu Cai, Siqi Li, Biao Yang, Shijie Zhou, Yuanming Pan, Shaofa Xu.
       Background: Malignant pleural mesothelioma (MPM) is a rare disease with limited treatment and poor prognosis, and a precise and reliable means to predicting MPM remains lacking for clinical use.
    Methods: In the population-based cohort study, we collected clinical characteristics from the Surveillance, Epidemiology, and End Results (SEER) database. According to the time of diagnosis, the SEER data were divided into 2 cohorts: the training cohort (from 2010 to 2016) and the test cohort (from 2017 to 2019). The training cohort was used to train a deep learning-based predictive model derived from DeepSurv theory, which was validated by both the training and the test cohorts. All clinical characteristics were included and analyzed using Cox proportional risk regression or Kaplan-Meier curve to determine the risk factors and protective factors of MPM.
    Results: The survival model included 3,130 cases (2,208 in the training cohort and 922 in the test cohort). As for model's performance, the area under the receiver operating characteristics curve (AUC) was 0.7037 [95% confidence interval (CI): 0.7030-0.7045] in the training cohort and 0.7076 (95% CI: 0.7067-0.7086) in the test cohort. Older age; male sex, sarcomatoid mesothelioma; and T4, N2, and M1 stage tended to be the risk factors for survival. Meanwhile, epithelioid mesothelioma, surgery, radiotherapy, and chemotherapy tended to be the protective factors. The median overall survival (OS) of patients who underwent surgery combined with radiotherapy was the longest, followed by those who underwent a combination of surgery, radiotherapy, and chemotherapy.
    Conclusions: Our deep learning-based model precisely could predict the survival of patients with MPM; moreover, multimode combination therapy might provide more meaningful survival benefits.
    Keywords:  Deep learning; malignant pleural mesothelioma (MPM); predictive model; prognosis
    DOI:  https://doi.org/10.21037/tcr-23-422
  5. Cancers (Basel). 2023 Oct 24. pii: 5116. [Epub ahead of print]15(21):
    The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma.
    Caddie Laberiano-Fernandez, Camila Machado Baldavira, Juliana Machado-Rugolo, Auriole Tamegnon, Renganayaki Krishna Pandurengan, Alexandre Muxfeldt Ab'Saber, Marcelo Luiz Balancin, Teresa Yae Takagaki, Maria Aparecida Nagai, Vera Luiza Capelozzi, Edwin Roger Parra.
       BACKGROUND: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design.
    METHODS: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments.
    RESULTS: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors.
    CONCLUSIONS: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
    Keywords:  in silico analysis; malignant pleural mesothelioma; multiplex immunofluorescence; prognosis; transcriptoma
    DOI:  https://doi.org/10.3390/cancers15215116
  6. Elife. 2023 11 13. pii: e85383. [Epub ahead of print]12
    Treatment with tumor-treating fields (TTFields) suppresses intercellular tunneling nanotube formation in vitro and upregulates immuno-oncologic biomarkers in vivo in malignant mesothelioma.
    Akshat Sarkari, Sophie Korenfeld, Karina Deniz, Katherine Ladner, Phillip Wong, Sanyukta Padmanabhan, Rachel I Vogel, Laura A Sherer, Naomi Courtemanche, Clifford Steer, Kerem Wainer-Katsir, Emil Lou.
      Disruption of intercellular communication within tumors is emerging as a novel potential strategy for cancer-directed therapy. Tumor-Treating Fields (TTFields) therapy is a treatment modality that has itself emerged over the past decade in active clinical use for patients with glioblastoma and malignant mesothelioma, based on the principle of using low-intensity alternating electric fields to disrupt microtubules in cancer cells undergoing mitosis. There is a need to identify other cellular and molecular effects of this treatment approach that could explain reported increased overall survival when TTFields are added to standard systemic agents. Tunneling nanotube (TNTs) are cell-contact-dependent filamentous-actin-based cellular protrusions that can connect two or more cells at long-range. They are upregulated in cancer, facilitating cell growth, differentiation, and in the case of invasive cancer phenotypes, a more chemoresistant phenotype. To determine whether TNTs present a potential therapeutic target for TTFields, we applied TTFields to malignant pleural mesothelioma (MPM) cells forming TNTs in vitro. TTFields at 1.0 V/cm significantly suppressed TNT formation in biphasic subtype MPM, but not sarcomatoid MPM, independent of effects on cell number. TTFields did not significantly affect function of TNTs assessed by measuring intercellular transport of mitochondrial cargo via intact TNTs. We further leveraged a spatial transcriptomic approach to characterize TTFields-induced changes to molecular profiles in vivo using an animal model of MPM. We discovered TTFields induced upregulation of immuno-oncologic biomarkers with simultaneous downregulation of pathways associated with cell hyperproliferation, invasion, and other critical regulators of oncogenic growth. Several molecular classes and pathways coincide with markers that we and others have found to be differentially expressed in cancer cell TNTs, including MPM specifically. We visualized short TNTs in the dense stromatous tumor material selected as regions of interest for spatial genomic assessment. Superimposing these regions of interest from spatial genomics over the plane of TNT clusters imaged in intact tissue is a new method that we designate Spatial Profiling of Tunneling nanoTubes (SPOTT). In sum, these results position TNTs as potential therapeutic targets for TTFields-directed cancer treatment strategies. We also identified the ability of TTFields to remodel the tumor microenvironment landscape at the molecular level, thereby presenting a potential novel strategy for converting tumors at the cellular level from 'cold' to 'hot' for potential response to immunotherapeutic drugs.
    Keywords:  cancer biology; cell biology; cell communication; intercellular communication; mouse; spatial transcriptomics; tumor-treating fields; tunneling nanotubes
    DOI:  https://doi.org/10.7554/eLife.85383
  7. J Exp Clin Cancer Res. 2023 Nov 16. 42(1): 304
    Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy.
    Anand Singh, Nathanael Pruett, Shivani Dixit, Sudheer K Gara, Haitao Wang, Roma Pahwa, David S Schrump, Chuong D Hoang.
       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.
    Keywords:  CBL0137; Curaxin; FACT complex; Immunotherapy; Mesothelioma; NF-κB; Tumor suppressor; p53
    DOI:  https://doi.org/10.1186/s13046-023-02889-6
  8. Open Life Sci. 2023 ;18(1): 20220746
    A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis.
    Abdulla Mousa Falah Alali, Dhyaram Lakshmi Padmaja, Mukesh Soni, Muhammad Attique Khan, Faheem Khan, Isaac Ofori.
      Lung cancer is a substantial health issue globally, and it is one of the main causes of mortality. Malignant mesothelioma (MM) is a common kind of lung cancer. The majority of patients with MM have no symptoms. In the diagnosis of any disease, etiology is crucial. MM risk factor detection procedures include positron emission tomography, magnetic resonance imaging, biopsies, X-rays, and blood tests, which are all necessary but costly and intrusive. Researchers primarily concentrated on the investigation of MM risk variables in the study. Mesothelioma symptoms were detected with the help of data from mesothelioma patients. The dataset, however, included both healthy and mesothelioma patients. Classification algorithms for MM illness diagnosis were carried out using computationally efficient data mining techniques. The support vector machine outperformed the multilayer perceptron ensembles (MLPE) neural network (NN) technique, yielding promising findings. With 99.87% classification accuracy achieved using 10-fold cross-validation over 5 runs, SVM is the best classification when contrasted to the MLPE NN, which achieves 99.56% classification accuracy. In addition, SPSS analysis is carried out for this study to collect pertinent and experimental data.
    Keywords:  lung cancer; magnetic resonance imaging; malignant mesotheliomas; support vector machine
    DOI:  https://doi.org/10.1515/biol-2022-0746
  9. Hum Mol Genet. 2023 Nov 13. pii: ddad193. [Epub ahead of print]
    Functional assay for assessment of pathogenicity of BAP1 variants.
    Pauliina E Repo, Michael P Backlund, Tero T Kivelä, Joni A Turunen.
       BACKGROUND: Pathogenic germline variants in BRCA1-Associated Protein 1 (BAP1) cause BAP1 tumor predisposition syndrome (BAP1-TPDS). Carriers run especially a risk of uveal (UM) and cutaneous melanoma, malignant mesothelioma, and clear cell renal carcinoma. Approximately half of increasingly reported BAP1 variants lack accurate classification. Correct interpretation of pathogenicity can improve prognosis of the patients through tumor screening with better understanding of BAP1-TPDS.
    METHODS: We edited five rare BAP1 variants with differing functional characteristics identified from patients with UM in HAP1 cells using CRISPR-Cas9 and assayed their effect on cell adhesion/spreading (at 4 h) and proliferation (at 48 h), measured as cell index (CI), using xCELLigence real-time analysis system.
    RESULTS: In BAP1 knockout HAP1 cultures, cell number was half of wild type (WT) cultures at 48 h (p = 0.00021), reaching confluence later, and CI was 78% reduced (p < 0.0001). BAP1-TPDS-associated null variants c.67+1G>T and c.1780_1781insT, and a likely pathogenic missense variant c.281A>G reduced adhesion (all p ≤ 0.015) and proliferation by 74%-83% (all p ≤ 0.032). Another likely pathogenic missense variant c.680G>A reduced both by at least 50% (all p ≤ 0.032), whereas cells edited with likely benign one c.1526C>T grew similarly to WT.
    CONCLUSIONS: BAP1 is essential for optimal fitness of HAP1 cells. Pathogenic and likely pathogenic BAP1 variants reduced cell fitness, reflected in adhesion/spreading and proliferation properties. Further, moderate effects were quantifiable. Variant modelling in HAP1 with CRISPR-Cas9 enabled functional analysis of coding and non-coding region variants in an endogenous expression system.
    Keywords:  BAP1; BAP1-TPDS; HAP1; uveal melanoma; variant interpretation
    DOI:  https://doi.org/10.1093/hmg/ddad193
  10. Chin Clin Oncol. 2023 Nov 02. pii: cco-23-82. [Epub ahead of print]
    Tumor treating fields: narrative review of a promising treatment modality for cancer.
    Tugce Kutuk, Ece Atak, Alonso La Rosa, Rupesh Kotecha, Minesh P Mehta, Michael D Chuong.
       BACKGROUND AND OBJECTIVE: Tumor treating fields (TTFields) therapy have emerged as a potentially effective treatment for various malignancies by delivering low-intensity, intermediate-frequency electrical fields that disrupt many processes inside cells, resulting in the interruption of cell division in cancer cells. Additionally, TTFields therapy has been found to be synergistic with existing therapeutic approaches. In this review, we provide an introduction and background to the primary mechanisms of TTFields and discuss the emerging preclinical and clinical outcomes of this novel cancer treatment technology.
    METHODS: We performed a literature search on PubMed, ClinicalTrials.Gov, and Google Scholar using the terms 'TTFields' and 'cancer'. We included studies, review articles, and editorials published in English from 1st January 2000 to 1st October 2023. All obtained publications were reviewed and their key references are cross-checked to ensure a balanced and high-quality review.
    KEY CONTENT AND FINDINGS: Clinical studies reported to date have demonstrated the survival advantage of TTFields therapy in newly diagnosed glioblastoma (GBM), non-small cell lung cancer (NSCLC), and meaningful clinical activity in recurrent GBM (rGBM) and malignant pleural mesothelioma. Moreover, TTFields therapy has exhibited promising safety profiles across a diverse range of cancers including pancreatic cancer, hepatocellular carcinoma (HCC), ovarian cancer, NSCLC, and gastric cancer, when combined with cytotoxic chemotherapy and/or immunotherapy regimens, suggesting broad applicability as an added treatment modality.
    CONCLUSIONS: Based on preclinical and clinical studies, TTFields therapy show promise as a potential treatment option for patients with a number of different malignancies, offering a favorable safety profile and the potential for significant clinical benefit. Further research is warranted to establish the optimal treatment parameters and identify specific patient subgroups that may derive the greatest advantage from this treatment modality.
    Keywords:  Tumor treating fields (TTFields); cancer; electric fields
    DOI:  https://doi.org/10.21037/cco-23-82
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