bims-mesote 2025-05-11 papers

Issue of 2025–05–11
six papers selected by
Laura Mannarino, Humanitas Research

Invest New Drugs. 2025 May 08.

Unraveling BOLD-100 synergistic potential in pleural mesothelioma treatment: an in vitro study.

Gregorio Bonsignore, Elia Ranzato, Simona Martinotti.

Pleural mesothelioma (PM) is a rare cancer affecting the pleural layer on the body's serosal surfaces. Exposure to asbestos fibers, a naturally occurring fibrous material with insulating characteristics, contributes to PM's prevalence. PM has a long latency period, making major surgery ineffective and necessitating systemic treatment. Despite the progress of mesothelioma treatment, the median survival is very poor; so, there is a strong need to explore new therapeutic approaches. This study explores the use of BOLD-100, a novel therapeutic drug that targets GRP78, a protein overexpressed in PM cells. BOLD-100, a ruthenium-based small molecule therapeutic drug, is being investigated for the treatment of advanced gastrointestinal malignancies in conjunction with chemotherapy. Our aim is to investigate cellular responses of several PM cell lines to a regimen that includes BOLD-100 in addition to other commonly used treatments. BOLD-100 is a ruthenium-based anticancer therapeutic.

Keywords: Chemotherapy; GRP78; Mesothelioma; Synergy

DOI: https://doi.org/10.1007/s10637-025-01540-9

Scand J Work Environ Health. 2025 May 06. pii: 4229. [Epub ahead of print]

Detailed mapping of mesothelioma cases in Denmark to identify areas with elevated risk: a nationwide population-based study.

Heidi Søgaard Christensen, Rikke Hedegaard Jensen, Lars Hernández Nielsen, Lise Dueholm Bertelsen, Christian Teglgaard, Jakob Hjort Bønløkke, Marianne Tang Severinsen, Martin Bøgsted.

OBJECTIVES: Previous studies mapping pleural mesothelioma in Denmark have found that the risk varies between Danish regions. However, evaluating disease risk for such relatively large geographical units ignores any heterogeneity within the unit and can thus diminish more local spikes in risk, missing smaller areas of excess risk. In this study, we examined the distribution of pleural mesothelioma in Denmark on an unprecedented detailed scale, mapping cases to each of the Danish parishes.
METHODS: We identified individuals diagnosed with pleural mesothelioma between 1990 and 2021 in the Danish Cancer Registry. Considering age- and sex-standardized incidence rate ratios (IRR), we used a conditional autoregressive random effects model to smooth IRR across parishes. Parishes with a smoothed parish-to-national IRR >1.25 or >2.0 with a posterior probability of >95% were flagged as parishes with an excess risk of pleural mesothelioma.
RESULTS: We identified 3105 incident cases of pleural mesothelioma in the study period. A total of 74 and 14 parishes were flagged with IRR significantly above 1.25 and 2.0, respectively. These parishes had posterior mean smoothed IRR of 1.82-4.13.
CONCLUSIONS: We provided a detailed mapping of pleural mesothelioma cases in Denmark and found five distinct areas, each covering several parishes, with a significantly elevated risk. All these areas were in the proximity of previous asbestos-using industries.

DOI: https://doi.org/10.5271/sjweh.4229

bioRxiv. 2025 Apr 14. pii: 2025.04.08.647821. [Epub ahead of print]

Combined quetiapine and radiation therapy approach to treat mesothelioma-initiating cells and increase survival in a mouse model of mesothelioma.

Anjelica Cardenas, Evelyn Arambula, Linda Azizi, Tara Lam, Sabrina Sutlief, Kruttika Bhat, Mohammad Saki, Ling He, Frank Pajonk.

Introduction: Malignant pleural mesothelioma (MPM) is a rare thoracic cancer associated with poor prognosis and low survival rates. In solid cancers, repurposed dopamine receptor antagonists have been shown to have anti-cancer effects. Moreover, in combination with radiotherapy, quetiapine (QTP), a dopamine (D) 2/3 receptor antagonist, has been shown to interfere with self-renewal capacity in glioma-initiating cells and increase survival in mouse models of glioblastoma. In this study we explore combined treatment effects in MPM.
Methods: Using mesothelioma cell lines, MSTO-211H, H2052, and H2452, and a MSTO-211H-derived orthotopic xenograft mouse model of MPM we examined how QTP combined with radiation affects mesothelioma-initiating cells (MICs) in vitro and survival in vivo . Subsequently, bulk and single cell RNA sequencing was used to characterize the transcriptomic landscape of MSTO-211H treated with combined radiation and QTP.
Results: We demonstrate that combining QTP with radiation reduces MIC self-renewal capacity and stem cell frequency. In vivo , this combination therapy significantly extends the median survival of mesothelioma-bearing mice. Clonogenic survival assays revealed that QTP does not enhance radiosensitivity in the tested mesothelioma cell lines. Sequencing data revealed, combined treatment downregulated cell cycle and proliferation pathways, depleted cancer stem cells, and increased cellular senescence.
Conclusion: Taken together, our study highlights the therapeutic potential of radiation with QTP in the treatment of MPM.

DOI: https://doi.org/10.1101/2025.04.08.647821

Cancer Res Commun. 2025 May 07.

PD-1 blockade mitigates surgery-induced immunosuppression and increases the efficacy of photodynamic therapy for pleural mesothelioma.

Gwendolyn M Cramer, Richard W Davis, Emmanouil Papasavvas, Astero Klampatsa, Joann M Miller, Shirron Carter, Ruth Ikpe, Min Yuan, Sandy Widura, R Sonali Majumdar, Sally McNulty, Mary Putt, Andrew V Kossenkov, Luis J Montaner, Sunil Singhal, Edmund K Moon, Steven M Albelda, Keith A Cengel, Theresa M Busch.

Lung-sparing radical pleurectomy with intraoperative photodynamic therapy (PDT) demonstrates remarkable survival for patients with pleural mesothelioma (PM). Nevertheless, most patients treated with this multimodal approach will develop local tumor recurrence. An understanding of potential causes of treatment failure is central to developing mitigation strategies. Surgery importantly reduces disease burden, but also produces tumor-promoting inflammation as demonstrated through transcriptomic analysis of PM specimens. Using preclinical models in the setting of combination therapy, we separated the benefit of surgical resection from its counterproductive effects on therapeutic outcome. Specifically, we evaluated mechanisms whereby surgically induced inflammation can be therapy-limiting in a murine model of tumor incision (TI) introduced by a surgical cut across the tumor. In this TI model, we identified distinct TI-altered patterns in innate and adaptive inflammatory cells in murine mesothelioma tumors, and we studied changes in these patterns with the addition of PDT. TI introduction of an immunosuppressive environment is established via upregulation of PD-1/PD-L1 expression on tumor cells, T cells, and myeloid cells that is partially resolved by PDT. Immune dysfunction is further mitigated by the addition of PD-1 blockade, leading to curative potential in a process that requires Ly6G+ neutrophils and CD8+ T cells. Overall, these studies suggest that, without PDT, surgical modulation of immune cell trafficking and functionality leads to systemic immunosuppression. This immunosuppressive state potentially interferes with generation of anti-tumor immunity by PDT. However, targeted inhibition of surgery-induced signaling in the PD-l/PD-L1 pathway counteracts surgery's immunosuppressive outcomes to enhance PDT efficacy in the intraoperative setting.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0571

Port J Card Thorac Vasc Surg. 2025 Apr 29. 32(1): 35-40

Oncological Outcomes Of Radical Surgery With And Without Induction And Adjuvant Chemotherapy In Mesothelioma Patients - 8-Year Experience In A Single Center.

Agata Nawojowska, Samuel Mendes, Marion Gaspar, Daniel Cabral, Cristina Rodrigues, Mariana Antunes, Magda Alvoeiro, Telma Calado, Francisco Félix.

INTRODUCTION: Mesothelioma is a devastating, insidious disease with a long latency period. Its peak incidence occurs in the 5th and 6th decades of life, up to 40 years after asbestos exposure which is strongly related to the disease. The optimal treatment is the object of an intense discussion.
AIMS: The established outcomes were disease-free survival (DFS) and 1-year survival analyzed in the context of neoadjuvant chemotherapy with subsequent surgery, surgical intervention without any systemic treatment, an upfront surgery and adjuvant chemotherapy and surgical intervention with both neo- and adjuvant therapy to establish the most advantageous treatment in terms of oncological results.
MATERIALS AND METHODS: We analyzed our center's surgical experience with radical surgery for mesothelioma, evaluating the disease-free time and 1-year survival in relation to the treatment scheme. A search of the department's surgical database for mesothelioma cases between January 2016 and December 2020 revealed 16 cases, which were included in the final analysis. The established outcomes were disease-free survival and 1-year survival.
RESULTS: The 3 patients treated with surgery without any systemic treatment had a median follow-up period (MFUP) of 7 months (3- 12), 67% of recurrence, DFS of 6 months (0-12), and 1-year survival of 33%. The 6 patients treated with neoadjuvant chemotherapy, surgical resection, and adjuvant therapy, had an MFUP of 45 months (8-82), 67% of recurrence, DFS of 32 months (2-82), and 1-year survival of 83%. The 1 patient, treated with neoadjuvant chemotherapy and subsequently, surgery had a follow-up of 29 months with DFS of 20 months and he was alive at the time of submission of this article. The 6 patients treated with an up-front surgery and adjuvant chemotherapy had an MFUP of 20 months (8-33), 67% of recurrence, DFS of 15 months (6-33), and 1-year survival of 67%.
CONCLUSION: Despite the limitations of the study, the multimodal approach with both neoadjuvant and adjuvant chemotherapy demonstrated the longest MFUP, DFS, and 1-year survival. The worst results were observed in patients treated only with radical surgery, while the sequence of systemic treatment did not influence the rate of recurrence.

Keywords: decortication; induction chemotherapy; mesothelioma; neo-adjuvant chemotherapy; pleural tumor; pleurectomy; pleuropneumectomy

DOI: https://doi.org/10.48729/pjctvs.457