bims-mesote 2026-10-04 papers

Issue of 2026–10–04
four papers selected by
Laura Mannarino, Humanitas Research

Pathol Int. 2026 Sep;76(9): e70172

Digital PCR for Detecting Loss of BAP1 and MTAP in Pleural Fluids of Mesothelioma Patients: Perspectives in the Diagnosis.

Giulia Rosini, Greta Alì, Rossella Bruno, Monica Cipollini, Rudy Foddis, Alessandra Celi, Roberto Silvestri, Filomena Rea, Vittorio Aprile, Marco Lucchi, Federica Gemignani, Stefano Landi.

Pleural mesothelioma (PM) often presents loss of BAP1 and MTAP genes. Digital PCR (dPCR) can accurately measure gene copy numbers (CNs). We hypothesized that cell-free DNA (cfDNA) extracted from the supernatant of pleural fluids (SPFs) could allow an efficient detection of these genetic events. BAP1/MTAP CN was measured with dPCR in SPFs and in solid tumor biopsies (STBs) of 37 PM patients. Results were compared with immunohistochemistry (IHC) carried out in STBs. IHC alone detected BAP1/MTAP-losses in 32/37 (86.5%). However, the sensitivity improved to 34/37 (91.9%) when low CN of BAP1/MTAP was included. Among 20 patients presenting SPFs, dPCR alone detected a low CN in 18 samples (sensitivity = 90%). Finally, this two-gene signature was applied on SPFs in a prospective series of six consecutive patients presenting an undefined diagnosis (negative for PM) and two showed reduced CN. After 7 months of follow-up, these subjects were further re-evaluated for the persistence/worsening of the symptoms and were diagnosed for PM. We highlighted dPCR's potential for detecting subtle BAP1/MTAP losses in SPFs of PM patients. This appears as a complementary approach for a more accurate diagnosis in specific contexts, when high-risk patients receive negative results after IHC analysis.

Keywords: BAP1; MTAP; digital PCR; gene copy number; immunohistochemistry; liquid biopsy; pleural fluids; pleural mesothelioma

DOI: https://doi.org/10.1111/pin.70172

J Natl Compr Canc Netw. 2026 Sep 29. 1-5

Immunotherapy for Pleural Mesothelioma.

Logan N Roof, James P Stevenson.

Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of pleural mesothelioma (PM) over the past decade. This review summarizes the history of immunotherapy in PM, covering studies of single-agent immunotherapy, combination checkpoint blockade, the integration of ICIs into frontline therapeutic strategies, and ICI-VEGF combinations. Also discussed are the emerging role of biomarkers in guiding first-line therapy selection for patients with PM and novel therapeutic approaches. Dual checkpoint blockade targeting PD-1 and CTLA-4 demonstrated clinical efficacy in early-phase studies and led to the pivotal phase III CheckMate 743 trial, which established nivolumab and ipilimumab as a standard first-line systemic therapy for PM, particularly in patients with nonepithelioid histology. Since that time, other combination therapy approaches have been explored. For example, chemoimmunotherapy studies have evaluated ICIs, including pembrolizumab and durvalumab, in combination with platinum chemotherapy, with pembrolizumab plus platinum-doublet chemotherapy expanding the approved frontline treatment options for PM. VEGF inhibition, validated in the phase III MAPS study, provided a biologic rationale for combining antiangiogenic agents with ICIs. This prompted investigation of bevacizumab in combination with atezolizumab and chemotherapy in the BEAT-meso study. Unfortunately, this combination did not provide meaningful benefit in this setting. Optimal patient selection and treatment sequencing remain undefined. Although robust data support the use of second-line immunotherapy after first-line chemotherapy, there is a paucity of evidence regarding the efficacy of chemotherapy following frontline ICI. Despite advancements in therapeutic options in PM, biomarker-driven treatment selection remains limited at this time. Future large clinical studies must incorporate validated and standardized biomarker subanalyses, including approaches such as circulating tumor DNA and multiomics, for biomarkers to become clinically relevant in this heterogeneous malignancy. Finally, novel therapeutic strategies, including bispecific antibodies, targeted therapies, perioperative immunotherapy, vaccines, and cellular therapies, are under active investigation and may further expand treatment options for patients with PM.

Keywords: Clinical Trials; immunotherapy; mesothelioma

DOI: https://doi.org/10.6004/jnccn.2026.7070

Front Oncol. 2026 ;16 1908974

Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models.

Glen J Weiss, Joseph C Loftus, David W Mallery, Nhan L Tran.

Aberrant activation of the Hippo-YAP/TAZ-TEAD transcriptional axis is a recurrent feature of multiple solid tumors and contributes to tumor maintenance, lineage plasticity, and therapeutic resistance. Recent medicinal chemistry has shown that TEAD proteins are druggable, but the rate at which in silico screening nominates compounds that prove functionally active in cells remains poorly defined, and negative validation results are rarely reported. Here we describe an experimental assessment of a focused set of computationally nominated candidate compounds, selected from a structure-guided virtual screen of the YAP-TEAD interface across approximately 917,000 library compounds and three predicted binding sites. Candidates were evaluated using long-term (144 hour) CellTiter-Glo proliferation assays in three Hippo-altered malignant pleural mesothelioma cell lines (MSTO-211H, NCI-H2052, NCI-H226), with the validated TEAD inhibitor K-975 and cisplatin as positive controls, and an exploratory TEAD-responsive luciferase reporter in MCF7 cells. K-975 produced dose-dependent antiproliferative activity in MSTO-211H and NCI-H2052, with reduced sensitivity in NCI-H226, while cisplatin reduced viability in all lines. In contrast, the computationally nominated compounds, including AG-690/36549045, AN-655/40856217, and additional library members, did not produce measurable antiproliferative activity at the concentrations tested. In the exploratory reporter, apparent suppression of TEAD activity consistently co-occurred with loss of cell viability, a pattern consistent with cytotoxicity rather than selective transcriptional inhibition; no TEAD-active reference compound was co-tested within the reporter panel, and no direct YAP-TEAD biochemical or target-engagement assay was performed. These results describe a case in which computational nomination at the YAP-TEAD interface showed limited concordance with cell-based activity and provide a transparent account of negative findings to inform expectations for early-stage discovery targeting Hippo-dependent transcriptional programs.

Keywords: Hippo signaling pathway; YAP/TAZ–TEAD; drug discovery; in silico docking; malignant pleural mesothelioma; negative results; target engagement; virtual screening

DOI: https://doi.org/10.3389/fonc.2026.1908974

Br J Cancer. 2026 Sep 28.

VISTA drives tumour-intrinsic proliferation in mesothelioma cells.

Lisa Kondo-Ida, Tatsuhiro Sato, Emi Mishiro-Sato, Satomi Mukai, Yoshitaka Sekido.

BACKGROUND: Mesothelioma is a therapeutic challenge because current therapies have limited efficacy. In this study, we investigated the role of the immune checkpoint molecule V-domain Ig suppressor of T cell activation (VISTA) in mesothelioma cells.
METHODS: The effect of VISTA expression on cell proliferation was analysed using mesothelioma cell lines and a mouse xenograft model. To investigate the underlying mechanisms, we performed immunoprecipitation-mass spectrometry and RNA-seq analysis to identify VISTA-associated proteins and downstream transcriptional changes.
RESULTS: Analysis of The Cancer Genome Atlas (TCGA) dataset revealed that VISTA and B7-H3 were highly expressed in mesothelioma cells; their expression patterns were positively correlated with those of genes highly expressed in epithelioid and sarcomatoid cells, respectively. Functional studies revealed that VISTA overexpression enhanced proliferation of mesothelioma cell lines, whereas VISTA knockdown markedly suppressed tumour growth in vitro and in vivo. Proteomic profiling revealed interactions between VISTA, cell adhesion molecules and intracellular signalling proteins such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), whereas RNA sequencing revealed enrichment of TNF signalling, and functional analyses demonstrated enhanced AKT phosphorylation.
CONCLUSIONS: These findings indicate that VISTA promotes mesothelioma cell proliferation through tumour-intrinsic signalling independent of immune modulation. VISTA is a promising subtype-specific therapeutic target for mesothelioma.

DOI: https://doi.org/10.1038/s41416-026-03639-z