bims-mesote 2025-07-27 papers

Issue of 2025–07–27
three papers selected by
Laura Mannarino, Humanitas Research

Mol Clin Oncol. 2025 Sep;23(3): 77

Enhanced efficacy of immune checkpoint inhibitors with OK-432 in malignant pleural mesothelioma: A case report.

Kazuki Yamada, Takehiro Uemura, Aya Mukai, Tatsuya Tanaka, Ippei Sakakibara, Keima Ito, Yuta Mori, Kensuke Fukumitsu, Satoshi Fukuda, Yoshihiro Kanemitsu, Tomoko Tajiri, Yutaka Ito, Tetsuya Oguri, Akio Niimi.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive cancer with limited treatment options and poor prognosis. Although immunotherapy with ipilimumab (IPI) and nivolumab (NIVO) has the potential to improve outcomes, disease progression, including recurrent pleural effusions, often occurs during or after the initial treatment. OK-432, an immunotherapeutic agent, is commonly used for pleurodesis to control malignant pleural effusions; however, its role in combination with immune checkpoint inhibitors (ICIs) remains underexplored. The present report describes 2 MPM cases in which patients initially responded to IPI and NIVO, but experienced disease progression. Following intrathoracic administration of OK-432, the patients were successfully rechallenged with ICI therapy. Both cases exhibited sustained disease control and resolution of pleural effusions. These findings suggested that OK-432 may modulate immune responses and potentially enhance the efficacy of ICIs. Further studies are warranted to validate the synergistic potential of OK-432 and ICIs in MPM and other thoracic malignancies.

Keywords: IPI; NIVO; OK-432; pleural effusion; pleurodesis

DOI: https://doi.org/10.3892/mco.2025.2872

EMBO Mol Med. 2025 Jul 24.

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.

Duo Xu, Yanyun Gao, Shengchen Liu, Shiyuan Yin, Tong Hu, Haibin Deng, Tuo Zhang, Balazs Hegedüs, Thomas M Marti, Patrick Dorn, Shun-Qing Liang, Ralph A Schmid, Ren-Wang Peng, Yongqian Shu.

Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

Keywords: De Novo Pyrimidine Synthesis; Metabolic Diversity; Neurofibromin 2 (NF2); Pleural Mesothelioma (PM); Synthetic Lethality

DOI: https://doi.org/10.1038/s44321-025-00278-4

Lung Cancer. 2025 Jul 17. pii: S0169-5002(25)00562-8. [Epub ahead of print]206 108670

Serum mesothelin as a response biomarker in pleural mesothelioma.

ASSESS-meso Collaborative group

BACKGROUND: CT scans are the current gold standard for disease monitoring for Pleural mesothelioma (PM), with radiology reported using the modified RECIST criteria. While mRECIST has its own challenges, attending for CT scans adds time and expense. A blood-based biomarker which tracks disease status could enable more responsive, community-based disease monitoring. This study evaluated the relationship between serial serum mesothelin (SM) levels and disease status.
METHODS: Patients with PM were recruited from Assess-Meso, a multi-centre prospective cohort study of patients with mesothelioma, between 28/2/2019 and 31/12/2023. Logistic regression, adjusted for sex, age, histology, performance status, eGFR and treatment, was used to assess the relationship between serial SM and radiological disease status. Prespecified sub-group analyses stratified participants by initial SM and treatment status.
RESULTS: 156 patients had ≥ 2 SM measurements with paired CT scans. Rising SM was associated with disease progression in the coincident time period (Adj OR 1.11, 95 % CI 1.03-1.19) and the subsequent 6 months (Adj OR 1.13, 1.03-1.23), regardless of initial SM. A 25 % change in SM was the optimal threshold, with a 25 % rise associated with disease progression (Adj OR 2.68 (1.52-4.73)) with sensitivity and specificity of 48.7 % (43.1 %-54.4 %) and 75.7 % (70.8 %-80.5 %) respectively. For patients receiving treatment, falling SM predicted subsequent disease response (Adj OR 1.37, 1.16-1.61).
CONCLUSIONS: Serial SM is a reliable response biomarker in PM, regardless of initial value and treatment status. These results support the use of SM in routine clinical care as an adjunct to CT scans, with several benefits over radiological monitoring.

Keywords: Biomarker; Mesothelin; Mesothelioma

DOI: https://doi.org/10.1016/j.lungcan.2025.108670