bims-mesote 2025-11-30 papers

Issue of 2025–11–30
five papers selected by
Laura Mannarino, Humanitas Research

Lancet Oncol. 2025 Dec;pii: S1470-2045(25)00514-5. [Epub ahead of print]26(12): 1676-1684

Pembrolizumab plus lenvatinib as second-line treatment in patients with pleural mesothelioma (PEMMELA): cohort 2 of a single-arm, phase 2 study.

Li-Anne H Douma, Vincent van der Noort, Ferry Lalezari, Jeltje F de Vries, Kim Monkhorst, Illaa Smesseim, Paul Baas, Bodien Schilder, Marrit Vermeulen, Jacobus A Burgers, Cornedine J de Gooijer.

BACKGROUND: Pembrolizumab (anti-PD-1 antibody) plus lenvatinib (multityrosine kinase inhibitor) showed high clinical activity in PEMMELA cohort 1 in patients with pleural mesothelioma pre-treated with platinum-based chemotherapy. This study (cohort 2) aimed to investigate the clinical activity of this combination in patients with pleural mesothelioma who progressed after first-line nivolumab plus ipilimumab.
METHODS: PEMMELA is a prospective, single-centre, single-arm, open-label, investigator-initiated phase 2 trial, done at the Netherlands Cancer Institute, Amsterdam, the Netherlands. Cohort 2 included patients aged 18 years and older with histologically confirmed pleural mesothelioma, an Eastern Cooperative Oncology Group performance status 0-1, and measurable disease according to the modified Response Evaluation Criteria in Solid Tumors for mesothelioma version 1.1, who progressed after treatment with nivolumab plus ipilimumab. Pembrolizumab (200 mg every 3 weeks intravenously) plus lenvatinib (20 mg orally daily) was administered for up to 2 years, or until disease progression, or unacceptable toxicity. The primary endpoint was objective response rate assessed by the local investigator. All patients who had received at least one cycle of pembrolizumab plus lenvatinib and had their disease evaluated were considered evaluable for the primary endpoint. All patients who received at least one cycle of the study treatment were included in the safety analysis set. Patients were not involved in study design. This study is registered with ClinicalTrials.gov (NCT04287829), and is complete.
FINDINGS: Between Dec 14, 2022, and March 5, 2023, 24 patients were screened, of whom 20 were enrolled and received at least one cycle of pembrolizumab plus lenvatinib. Of these 20 patients, 17 patients (85%) were male and three (15%) were female. At data cutoff (Sept 1, 2024), with a median follow-up of 11·9 months (IQR 10·8-15·8), 12 (60%, 95% CI 36-81%) of 20 patients had an objective response. 14 (70%) of 20 patients developed grade 3 or 4 treatment-related adverse events, of which most common grade 3 events were hypertension (five patients [25%]) and fatigue including malaise (four patients [20%]). Ten treatment-related serious adverse events were observed in seven patients. Nine (45%) of 20 patients required at least one dose reduction and two (10%) discontinued treatment due to toxicity. There were no treatment related deaths.
INTERPRETATION: This study met its primary endpoint, showing high clinical activity of pembrolizumab plus lenvatinib, but with substantial toxicity, in patients with pleural mesothelioma who had progressed after first-line nivolumab plus ipilimumab. This drug combination is promising for future studies in pleural mesothelioma.
FUNDING: Merck Sharp and Dohme.

DOI: https://doi.org/10.1016/S1470-2045(25)00514-5

Lung Cancer. 2025 Nov 22. pii: S0169-5002(25)00744-5. [Epub ahead of print]210 108852

Circulating microRNAs as biomarkers for risk assessment and prognostic stratification of pleural mesothelioma.

Evgeniya Sharova, Paola Del Bianco, Loredana Urso, Micol Silic-Benussi, Daniela Scattolin, Donna M D'Agostino, Giulia Pasello, Vincenzo Ciminale.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive neoplasm associated with asbestos exposure. Clinical management of PM poses major challenges due to the lack of reliable markers for early diagnosis and prognostic stratification. Here we evaluated circulating microRNAs (miRNAs) as minimally invasive biomarkers for PM detection and risk assessment.
METHODS: Plasma samples were collected from 32 asbestos-exposed (AsbEX) individuals and 56 PM patients, including epithelioid (N = 45) and non-epithelioid (N = 11) subtypes. An initial discovery cohort (9 AsbEX and 9 PM) was screened for 92 miRNAs using quantitative RT-PCR. Candidate miRNAs were validated in the full cohort.
RESULTS: Ratios calculated from the plasma levels of miR-24-3p, miR-146a-5p, miR-191-5p, miR-200a-3p, miR-222-3p, miR-223-3p, and miR-1260a robustly differentiated PM patients from asbestos-exposed controls with high accuracy and sensitivity. Furthermore, ratios of circulating miR-146a-5p, miR-200a-3p, miR-222-3p and miR-191-5p enabled stratification of epithelioid PM in high- and low-risk prognostic groups.
CONCLUSION: Circulating miRNA signatures represent promising non-invasive biomarkers for early PM detection and prognostic stratification, particularly in epithelioid cases. Incorporation of these biomarkers into clinical workflows could pave the way for more personalized treatment strategies and optimize patient selection for surgery.

Keywords: Circulating miRNA; Epithelioid mesothelioma; Liquid biopsy; Patient stratification

DOI: https://doi.org/10.1016/j.lungcan.2025.108852

Pharmaceutics. 2025 Nov 19. pii: 1494. [Epub ahead of print]17(11):

Bis-Oxadiazole Assemblies as NO-Releasing Anticancer Agents.

Egor M Matnurov, Irina A Stebletsova, Alexander A Larin, Jemma Arakelyan, Ivan V Ananyev, Artem L Gushchin, Leonid L Fershtat, Maria V Babak.

Background: Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-associated cancer characterized by dysregulated nitric oxide (NO) signaling and increased NO levels that facilitate tumor progression. Paradoxically, this aberrant NO environment creates a therapeutic vulnerability that can be exploited by NO-donor prodrugs, which overwhelm cellular defenses with cytotoxic concentrations of NO, inducing nitrosative stress and apoptosis. Within this framework, oxadiazole-based scaffolds have emerged as a promising platform for prodrug development owing to their versatile chemistry and potential as novel NO donors or synergistic agents. In our previous studies, we developed several series of hybrid architectures incorporating 1,2,5-oxadiazole 2-oxide (furoxan) and 1,2,4-oxadiazole scaffolds, producing compounds with diverse and tunable NO-donor activities. We further observed that the cytotoxicity of these hybrids was significantly influenced by the substituents introduced at position 3 of the furoxan ring. Methods: We designed and synthesized a series of bis(1,2,4-oxadiazolyl)furoxans to systematically investigate their NO-donating capacity, cytotoxicity against MPM cell lines, selectivity over healthy lung fibroblasts, and underlying anticancer mechanisms. Results: The bis(1,2,4-oxadiazolyl)furoxans exhibited lower overall cytotoxicity but significantly higher selectivity compared with previously studied 3-cyano-4-(1,2,4-oxadiazolyl)furoxans. Their NO-releasing properties showed a strong correlation with their ability to induce mitochondrial damage, as evidenced by membrane depolarization. Moreover, the incorporation of specific substituents, such as a furan ring, on the 1,2,4-oxadiazole moiety introduced an additional mechanism of action through the induction of reactive oxygen species. Conclusions: Analysis of cancer cell death confirmed that these compounds acted through a multimodal mechanism dependent on both NO release and the specific substituents on the 1,2,4-oxadiazole moiety.

Keywords: NO donors; antiproliferative activity; furoxan; malignant pleural mesothelioma; mechanism of action; nitrogen heterocycles; oxadiazole

DOI: https://doi.org/10.3390/pharmaceutics17111494

BMC Cancer. 2025 Nov 26.

Proteomics of malignant pleural mesothelioma under hypoxic and normoxic conditions in a large animal (porcine) tumor model.

Weirun Min, Donggang He, Xuanbo Liu, Xiaokang Zhu, Baiqiang Cui, Wei Cao, Zhuang Zuo, Jin Wang, Zhibo Ye, Xu Tang, Sheng Yong, Shengyuan Xiong, Dacheng Jin, Shengguo Zhao, Yunjiu Gou.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is a rare but highly aggressive malignant tumor, whose occurrence is closely associated with asbestos exposure. Clinical treatment options are limited and the prognosis is poor. The tumor microenvironment, especially hypoxia, plays a key regulatory role in the occurrence and development of MPM, yet its specific molecular mechanism remains unclear. To explore the effects of different oxygen metabolic states on the protein expression profiles and functional characteristics of MPM, this study first cultured MPM cells under normoxic and hypoxic conditions and conducted proteomic analysis. Furthermore, it explored MPM animal models simulating normoxic and hypoxic conditions, aiming to provide an experimental platform closer to the physiological state for MPM mechanism research and targeted intervention.
METHODS: In in vitro studies, MSTO-211 H cells were cultured under 1% O₂ concentration (experimental group) and 21% O₂ concentration (control group) for 48 h, passaged for 3 generations, with 3 biological replicates in each group. TMT quantitative proteomics was used to screen differential proteins, and GO and KEGG analyses were performed to explore related signaling pathways. In animal experiments, the hypoxic group and normoxic group were injected with benzo(a)pyrene solution via a closed thoracic device, while the blank control group was injected with normal saline. Clinical symptoms and multiple biological indicators of the animals were monitored, and tumor characteristics were described based on CT, histopathological and immunohistochemical results. RESULTS: In in vitro studies, a total of 42 differential proteins were identified between the hypoxic group and the normoxic group. GO and KEGG analyses revealed that the two groups shared differences in three signaling pathways: protein digestion and absorption, neuroactive ligand-receptor interaction, and Staphylococcus aureus infection. In in vivo studies, MPM occurred in both the hypoxic group (Tibetan pigs) and the normoxic group (Landrace pigs) after intrathoracic injection of benzo(a)pyrene, while the normoxic group was accompanied by benign pleural hyperplasia. Only inflammatory cell infiltration was observed in the normal saline control group. The tumor tissue was composed of well-differentiated epithelioid cells and fibrovascular stroma. IHC detection showed that the tumor cells expressed specific proteins consistent with MPM, and the tumor microenvironment contained abundant CD31-positive small vascular endothelial cells. During the follow-up period of 224-238 days, the experimental pigs remained in good health. CONCLUSION: Based on the study of differentially expressed proteins in malignant pleural mesothelioma under hypoxic and normoxic conditions, the successfully constructed large-scale porcine tumor model can pre-verify the effect of drugs on tumors in different oxygen environments during new drug development, improving screening efficiency and success rate. It can also accurately simulate clinical scenarios, providing experimental support for the efficacy evaluation and scheme optimization of intervention strategies such as chemotherapy, radiotherapy, and immune targeting, thereby effectively promoting the development of clinical treatment for malignant pleural mesothelioma..

DOI: https://doi.org/10.1186/s12885-025-15256-9

BMJ Case Rep. 2025 Nov 23. pii: e268562. [Epub ahead of print]18(11):

Tomoyuki Ogata, Kentaro Nakamura, Tomohiro Moriya, Takaaki Yamashita.

A man in his 60s with a history of asbestos exposure had been followed for progressive right-sided pleural thickening over several years. Imaging findings on high-resolution CT and 18F-fluorodeoxyglucose positron emission tomography/CT strongly suggested malignant pleural mesothelioma. However, both CT-guided pleural biopsy and endobronchial ultrasound-guided transbronchial needle aspiration of the mediastinal lymph nodes showed no evidence of malignancy, and a definitive diagnosis could not be established. After a 2-year interruption in follow-up, pleural thickening had further progressed. Immunostaining of previously obtained tissue samples ultimately led to a diagnosis of immunoglobulin G4 (IgG4)-related pleurisy. Steroid therapy resulted in a reduction of pleural thickening. This case highlights the importance of considering IgG4-related pleurisy in the differential diagnosis of pleural disease mimicking malignant pleural mesothelioma, particularly in patients with a history of asbestos exposure.

Keywords: Interstitial lung disease; Respiratory cancer

DOI: https://doi.org/10.1136/bcr-2025-268562