Malignant Pleural Mesothelioma

P3, N=53, Completed, Ferring Ventures Limited | Active, not recruiting --> Completed

We identified cytarabine and methotrexate as significantly more effective in the 9p21 compromised BLCA cells. Analysis of morphological alterations further supported a genotype-specific activity of nucleoside analogs, nominating gemcitabine as a drug with greater efficacy in this context...Synergy between cytarabine and inhibitors of PRMT5 (MRTX1719) and MAT2A (AG-270) was mediated by a differential activation of DNA damage and replication stress markers, suggesting an exploitable vulnerability. In fact, rational drug combinations with ATR/CHK1 pathway inhibitors increased efficacy while maintaining 9p21-specificity. Finally, we confirmed the effectiveness of these combinations in cell models of pancreatic adenocarcinoma and pleural mesothelioma, two tumor types with high prevalence of MTAP loss and, most notably, in bladder cancer patient-derived organoids, underscoring the strong translational potential of our findings.

P1, N=60, Recruiting, Memorial Sloan Kettering Cancer Center

TAMs were enriched in antigen-presentation (CD80, CD86, CXCL10), extracellular matrix-degradation (MMP9, CTSL), and CTL-suppression (ARG1, PLA2G7) pathways. Our analyses revealed that regional immunosuppression mediated by adaptive reprogramming of tumor-cell and immune-cell (TAMs, CTLs)-intrinsic changes-rather than by immune evasion or stromal exclusion-served as a mechanism of acquired resistance to dual-ICI therapy.

The CDK4/6 inhibitors abemaciclib and palbociclib have demonstrated promising results in patient-derived xenograft models of PM...While some cells showed sensitivity to Bcl-xL inhibitors, neither navitoclax nor the specific Bcl-xL inhibitor A-1331852, nor other BH3 mimetics targeting Bcl-2 (venetoclax) or Mcl-1 (S63845) increased cell death when combined with palbociclib...Therefore, we employed inhibitors of these pathways, such as dasatinib, momelotinib or Torin-1, which did not synergise with palbociclib to kill the cells...The differential effects of palbociclib and cisplatin on permanent growth arrest were verified by sorting PM cells based on size and β-galactosidase activity. Our findings underscore the importance of understanding the nature of therapy-induced senescence when assessing the effectiveness of senolytics in different tumour models.

The disease proved refractory to multiple lines of therapy, including platinum-based chemotherapy, immunotherapy, intrathoracic instillation and a subsequent individualized regimen comprising intraperitoneal cisplatin plus sintilimab for local disease control and potential immunomodulation synergized with oral anlotinib. It illustrates that rare but actionable genomic alterations, such as MET amplification, can be identified through liquid or tissue biopsy and can inform successful targeted treatment strategies, even in a tumor type where such alterations are uncommon. Histological classification combined with molecular profiling remains pivotal for personalized oncology.

In conclusion, in addition to supporting histology grading of EM, our findings highlight that EM-HG cases display more heterogeneous expression profiles than EM-LG with some features in between EM-LG and SM/BM. Further data is needed to explore the potential clinical utility EZH2 IHC in the clinical management of pleural mesothelioma.

The emerging role of Artificial Intelligence in subtyping, grading and prediction of biomarkers for genomic subtyping is also discussed. [251 words].

P1, N=10, Recruiting, Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute) | Not yet recruiting --> Recruiting

P1/2, N=36, Recruiting, Beijing Biotech

Prospective, multi-institutional studies with standardized brain imaging are needed to further characterize the incidence of BrMs in DPM and associated risk factors. Routine brain surveillance at diagnosis and with symptoms should be considered for patients with DPM.

P1/2, N=126, Recruiting, Intergroupe Francophone De Cancerologie Thoracique | Not yet recruiting --> Recruiting