bims-mesote 2026-03-08 papers

Issue of 2026–03–08
four papers selected by
Laura Mannarino, Humanitas Research

Cell Death Dis. 2026 Feb 28.

Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient pleural mesothelioma.

Sivasundaram Karnan, Akinobu Ota, Muhammad Nazmul Hasan, Hideki Murakami, Md Lutfur Rahman, Md Wahiduzzaman, Md Towhid Ahmed Shihan, Nushrat Jahan, Lam Quang Vu, Ichiro Hanamura, Akihito Inoko, Miho Riku, Hideaki Ito, Yoshifumi Kaneko, Yinzhi Lin, Toshinori Hyodo, Hiroyuki Konishi, Shinobu Tsuzuki, Yoshitaka Hosokawa.

Pleural mesothelioma (PM) is an uncommon yet deadly cancer linked to asbestos exposure. The lack of effective early diagnosis and treatment leads to reduced life expectancy among patients with PM. This study aims to identify a novel molecular target inhibitor to develop more effective therapeutics for PM. Our drug screening assay showed that the fatty acid synthase (FASN) inhibitor cerulenin demonstrates strong and selective antiproliferative properties against NF2/CDKN2A(p16)-deficient PM cells, surpassing the effects of C75, cisplatin or pemetrexed. FASN protein is frequently detected in NF2/p16-deficient PM tumor-derived tissues (15/15, 100%), but rarely in NF2/p16-intact PM tumors (8/25, 32%). Notably, cerulenin administration successfully reduced the growth of NF2/p16-deficient PM tumors in xenografted mice. Cerulenin inhibits mitochondrial fission by targeting dynamin-related protein 1 (DRP1) in NF2/p16-deficient cells. Moreover, the disruption of the FASN gene leads to increased ubiquitination of DRP1. These findings suggest that FASN might play a role in the tumorigenesis of PM cells through the regulation of mitochondrial dynamics. This research offers a novel perspective on the potential development of precision medicine for PM.

DOI: https://doi.org/10.1038/s41419-026-08481-y

AAPS PharmSciTech. 2026 Mar 04. pii: 122. [Epub ahead of print]27(3):

Advancing Rare Cancer Therapeutics: Osimertinib-Loaded Inhaled PLGA Nanoparticles for Mesothelioma Treatment.

Mural Quadros, Naveen Rajana, Vivek Gupta.

Despite advances in mesothelioma treatment, malignant pleural mesothelioma (MPM) continues to present a poor prognosis due to its aggressive progression and resistance to conventional therapies. Current treatment modalities, including surgery, chemotherapy, radiation, and immunotherapy, offer limited efficacy, with a five-year survival rate of approximately 12%. To address the limitations of systemic drug delivery, this study investigates the therapeutic potential of osimertinib (OSI), a third-generation tyrosine kinase inhibitor, delivered via inhalation using poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The optimized PLGA-OSI formulation exhibited an encapsulation efficiency of 43.1 ± 4.8%, drug loading of 4.4 ± 0.4%, particle size of 198.5 ± 9.3 nm, and zeta potential of -17.6 ± 1.2 mV. In vitro cytotoxicity assays revealed IC₅₀ values of 13.5 ± 0.1 µM (MSTO-211H), 27.7 ± 0.3 µM (H2452), and 8.1 ± 0.2 µM (H226) after 48 h. Compared to free OSI, PLGA-OSI enhanced cellular uptake, increased GFP-positive cells by 1.7-fold, and elevated fluorescence intensity by 5.3-fold. Clonogenic and scratch assays confirmed significant inhibition of cell proliferation and migration. Moreover, spheroid models demonstrated superior tumor suppression with multi-dose treatments. These findings highlight the potential of inhaled PLGA-OSI nanoparticles to improve drug delivery and therapeutic outcomes in MPM, supporting their further development as a targeted treatment strategy against this challenging malignancy.

Keywords: PLGA nanoparticles; drug repurposing; inhalation; mesothelioma; osimertinib (OSI); spheroid assay

DOI: https://doi.org/10.1208/s12249-025-03322-1

Lancet Respir Med. 2026 Feb 25. pii: S2213-2600(25)00409-6. [Epub ahead of print]

Medical thoracoscopy with talc poudrage and indwelling pleural catheter insertion versus medical thoracoscopy with talc poudrage alone for patients with symptomatic malignant pleural effusion (TACTIC): a randomised, controlled phase 3 trial.

BACKGROUND: Patients with suspected malignant pleural effusions (MPE) are often in need of both a confirmatory diagnosis and symptom control. Therapeutic options include talc pleurodesis via chest drain, poudrage during medical thoracoscopy, or alternatively an indwelling pleural catheter (IPC). Combining the diagnostic and therapeutic efficacy of medical thoracoscopy and poudrage with the ambulatory benefits of an IPC has not been studied within a randomised controlled trial. The aim of the TACTIC trial was to determine whether this approach resulted in a reduced length of hospital stay and improvements in dyspnoea.
METHODS: This unblinded, phase 3, randomised controlled trial was undertaken in 11 UK hospitals. Patients with MPE and confirmed malignancy (during medical thoracoscopy or beforehand) received talc poudrage and were randomly assigned by a centralised web-based system to an IPC at the time of medical thoracoscopy or usual care (ie, medical thoracoscopy, poudrage, and admission with large bore tube). Co-primary outcomes were time in hospital (including initial admission for trial procedure and any subsequent readmissions over 4 weeks post procedure) and average breathlessness assessed with visual analogue scale dyspnoea scores, measuring severity of dyspnoea from 0 mm to 100 mm, over a 4-week period. All randomised patients in whom an outcome was available were included in the analysis on a modified intention-to-treat basis. TACTIC was registered with ISRCTN on Aug 8, 2021 (ISRCTN11058680).
FINDINGS: Participants were recruited from between Dec 15, 2021, and Jan 3, 2024. 124 participants were randomised: 62 to the intervention and 62 to standard care. Leading diagnoses were pleural mesothelioma (46%), lung cancer (28%), and breast cancer (10%). Co-primary outcome data were available for 102 patients for total length of hospital stay (52 in intervention group vs 50 in standard care group) and 108 patients for breathlessness (57 vs 51). Median time in hospital was 1 day (IQR 1-3, 95% CI 1-2) in the intervention group versus 2 days (IQR 1-3, 95% CI 1-2) in standard care group (p=0·26). Median visual analogue scale dyspnoea scores did not differ between groups: 14·0 mm (IQR 8·8-32·4) in the intervention group versus 19·6 mm (8·1-38·7) in standard care group (p=0·26). Participants in the intervention group required fewer additional invasive pleural procedures by 12 weeks (two [3%] of 60 vs 19 [34%] of 56, p<0·0001) Trial related adverse events rates were similar in both groups (46 [74%] of 62 vs 44 [71%] of 62, p=0·84). Three related serious adverse events were recorded, all occurring in the intervention group.
INTERPRETATION: The combination of medical thoracoscopy, poudrage, and IPC did not result in shorter hospital stay but was safe and resulted in similar dyspnoea control compared with standard care. For patients with symptomatic MPE undergoing medical thoracoscopy for pleurodesis who prioritise minimising the length of hospital stay or the need for further invasive pleural procedures, the addition of an IPC alongside poudrage might help to achieve this goal.
FUNDING: National Institute of Health Research, Research for Patient Benefit.

DOI: https://doi.org/10.1016/S2213-2600(25)00409-6

Br J Cancer. 2026 Mar 06.

Enhanced nuclear export caused by O-GlcNAcylation of nucleoporins is a potential therapeutic target in mesothelioma.

Satomi Mukai, Tatsuhiro Sato, Yasuhiro Kamei, Kagayaki Kato, Emi Mishiro-Sato, Lisa Kondo-Ida, Norikazu Yabuta, Kenzo Hiroshima, Yoshitaka Sekido.

BACKGROUND: Mesothelioma is an aggressive malignancy with limited therapeutic options. Genetic alterations involving the Hippo pathway are commonly observed. O-GlcNAcylation is frequently elevated in cancer and drives tumour progression. However, its relationship with Hippo pathway dysfunction in mesothelioma remains unclear.
METHODS: O-GlcNAcylation levels were examined in mesothelioma samples and cell lines, and O-GlcNAcylated proteins were detected by mass spectrometry. The functional impact of O-GlcNAcylation was determined by quantifying nuclear transport dynamics using light-induced live-cell imaging. Genetic and pharmacological inhibition of O-GlcNAcylation was evaluated in vitro. Treatment with the nuclear export inhibitor KPT-330 (Selinexor) was assessed in vitro and in a mouse xenograft model.
RESULTS: O-GlcNAcylation was markedly increased in mesothelioma cells with Hippo pathway inactivation. This modification primarily targeted nuclear pore complex proteins, including NUP214 and NUP62, and significantly accelerated nuclear export rates. Suppression of O-GlcNAcylation diminished nuclear export and inhibited cell proliferation. Importantly, pharmacological blockade of nuclear export using KPT-330 suppressed cell growth in vitro and produced significant antitumour effects in vivo.
CONCLUSIONS: These findings demonstrate O-GlcNAcylation-driven enhancement of nuclear export as a therapeutically actionable vulnerability in mesothelioma with inactivation of the Hippo pathway.

DOI: https://doi.org/10.1038/s41416-026-03369-2