bims-mesote 2023-07-16 papers

Issue of 2023–07–16
six papers selected by
Laura Mannarino, Humanitas Research

Int J Mol Sci. 2023 Jun 21. pii: 10415. [Epub ahead of print]24(13):

Improvements in Systemic Therapies for Advanced Malignant Mesothelioma.

Chiara Deiana, Francesca Fabbri, Simona Tavolari, Andrea Palloni, Giovanni Brandi.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy associated with poor prognosis and a 5-year survival rate of 12%. Many drugs have been tested over the years with conflicting results. The aim of this review is to provide an overview of current therapies in MPM and how to best interpret the data available on these drugs. Furthermore, we focused on promising treatments under investigation, such as immunotherapy with targets different from anti-PD-1/PD-L1 inhibitors, vaccines, target therapies, and metabolism-based strategies.

Keywords: TKI; advanced mesothelioma; antiangiogenic; immunotherapy; mesothelioma; novel approaches; systemic therapies; target therapy; vaccines

DOI: https://doi.org/10.3390/ijms241310415

Genes Chromosomes Cancer. 2023 Jul 08.

Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways.

Maymun Jama, Min Zhang, Charlotte Poile, Apostolos Nakas, Annabel Sharkey, Joanna Dzialo, Alan Dawson, Kudazyi Kutywayo, Dean A Fennell, Edward J Hollox.

Malignant pleural mesothelioma (MPM), a rare cancer a long latency period (up to 40 years) between asbestos exposure and disease presentation. The mechanisms coupling asbestos to recurrent somatic alterations are poorly defined. Gene fusions arising through genomic instability may create novel drivers during early MPM evolution. We explored the gene fusions that occurred early in the evolutionary history of the tumor. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal nonrecurrent gene fusions, three of which were novel (FMO9P-OR2W5, GBA3, and SP9). The number of early gene fusion events detected varied from zero to eight per tumor, and presence of gene fusions was associated with clonal losses involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumor suppressors BAP1, MTAP, and LRP1B, and a clonal oncogenic fusion involving CACNA1D-ERC2, PARD3B-NT5DC2, and STAB2-NT5DC2 fusions were also identified as clonal fusions. Gene fusions events occur early during MPM evolution. Individual fusions are rare as no recurrent truncal fusions event were found. This suggests the importance of early disruption of these pathways in generating genomic rearrangements resulting in potentially oncogenic gene fusions.

Keywords: evolution; gene fusion; genomics; mesothelioma; transcriptomics

DOI: https://doi.org/10.1002/gcc.23189

Br J Neurosurg. 2023 Jul 09. 1-3

Management of sarcomatoid Malignant pleural mesothelioma brain metastases with stereotactic radiosurgery: an Illustrative case.

Jack K Donohue, Zhishuo Wei, Hansen Deng, Ajay Niranjan, L Dade Lunsford.

Background: Malignant pleural mesothelioma (MPM) is a rare cancer of the respiratory system that rarely metastasizes to the brain. We report a case of sarcomatoid MPM (SMPM) managed with Stereotactic radiosurgery (SRS) to achieve intracranial tumor control and improve neurological symptoms.Illustrative case: This 67-year-old female patient underwent SRS twice in order to treat a total of 15 brain metastases. One-month follow-up imaging after the first SRS demonstrated local tumor response and seven tumors with symptomatic vasogenic edema that responded to initial corticosteroids followed by bevacizumab. At a three-month follow-up after the first procedure, eight new tumors were detected and required repeat SRS. Although sustained tumor control resulted in improved neurological function, the patient subsequently expired from systemic disease progression 12 months after initial diagnosis and six months after initial SRS for brain metastases despite the concurrent use of systemic immunotherapy and systemic chemotherapy.Conclusions: Although SRS provided overall tumor control of metastatic brain disease, further advances in systemic therapies will be needed to improve survival in this aggressive rare cancer.

Keywords: Stereotactic radiosurgery; adverse radiation effect; brain metastasis; cancer immunotherapy; sarcomatoid malignant pleural mesothelioma

DOI: https://doi.org/10.1080/02688697.2023.2233602

Front Toxicol. 2023 ;5 1200650

Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma.

Pooyeh Farahmand, Katarina Gyuraszova, Claire Rooney, Ximena L Raffo-Iraolagoitia, Geeshath Jayasekera, Ann Hedley, Emma Johnson, Tatyana Chernova, Gaurav Malviya, Holly Hall, Tiziana Monteverde, Kevin Blyth, Rodger Duffin, Leo M Carlin, David Lewis, John Le Quesne, Marion MacFarlane, Daniel J Murphy.

Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy. Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit.

Keywords: GM mouse model; asbestos; cancer therapy; macrophages; mesothelioma

DOI: https://doi.org/10.3389/ftox.2023.1200650

J Cancer Res Clin Oncol. 2023 Jul 08.

An anoikis-based gene signature for predicting prognosis in malignant pleural mesothelioma and revealing immune infiltration.

Jiaxin Shi, Bo Peng, Xiang Zhou, Chenghao Wang, Ran Xu, Tong Lu, Xiaoyan Chang, Zhiping Shen, Kaiyu Wang, Chengyu Xu, Linyou Zhang.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant tumor. Anoikis is a particular type of programmed apoptosis brought on by the separation of cell-cell or extracellular matrix (ECM). Anoikis has been recognized as a crucial element in the development of tumors. However, few studies have comprehensively examined the role of anoikis-related genes (ARGs) in malignant mesothelioma.
METHODS: ARGs were gathered from the GeneCard database and the Harmonizome portals. We obtained differentially expressed genes (DEGs) using the GEO database. Univariate Cox regression analysis, and the least absolute shrinkage and selection operator (LASSO) algorithm were utilized to select ARGs associated with the prognosis of MPM. We then developed a risk model, and time-dependent receiver operating characteristic (ROC) analysis and calibration curves were employed to confirm the ability of the model. The patients were divided into various subgroups using consensus clustering analysis. Based on the median risk score, patients were divided into low- and high-risk groups. Functional analysis and immune cell infiltration analysis were conducted to estimate molecular mechanisms and the immune infiltration landscape of patients. Finally, drug sensitivity analysis and tumor microenvironment landscape were further explored.
RESULTS: A novel risk model was constructed based on the six ARGs. The patients were successfully divided into two subgroups by consensus clustering analysis, with a striking difference in the prognosis and landscape of immune infiltration. The Kaplan-Meier survival analysis indicated that the OS rate of the low-risk group was significantly higher than the high-risk group. Functional analysis, immune cell infiltration analysis, and drug sensitivity analysis showed that high- and low-risk groups had different immune statuses and drug sensitivity.
CONCLUSIONS: In summary, we developed a novel risk model to predict MPM prognosis based on six selected ARGs, which could broaden comprehension of personalized and precise therapy approaches for MPM.

Keywords: Anoikis; Immune infiltration landscape; Malignant pleural mesothelioma; Prognosis; Risk model

DOI: https://doi.org/10.1007/s00432-023-05128-9

Virchows Arch. 2023 Jul 10.

Peritoneal papillary mesothelioma in situ: BAP1 mutation with indolent behavior for 15 years.

Nikola Vitlarov, E Burtscher, E Pfeiffenberger, A Wahl, V Hodja, Z Jasarevic, K Kashofer, F A Offner.

Papillary mesothelioma in situ (PMIS) is a rare and enigmatic disease. Most instances manifest as lesions of the peritoneal serosa. The pathogenesis and behavior of peritoneal PMIS are still poorly understood, and separation from benign well differentiated peritoneal mesothelial tumors (WDPMT) may be challenging. We describe the 15-year long course of a PMIS in an adult male in which inactivating mutations of BAP1, encoding BRCA1 associated protein 1 (BAP1), were identified. Tumor samples were obtained on 2 occasions more than 8y apart. In both samples, the tumor cells were bland, with occasional focal infiltration into the stalks of larger papillary lesions. However, no invasion into subserosal adipose tissue was identified. In both samples the tumor cells did not express nuclear BAP1. Comprehensive genomic analysis of the initial tumor sample revealed a somatic inactivating mutation in BAP1 (predicted effect, Y223*) and a somatic variant of IRS2 (A701_V702insAA). An additional inactivating mutation in BAP1 (predicted effect, T69fs*5) was detected in the later sample. The patient did not receive any treatment and is still alive 15 years after initial presentation. Our experience supports the view that peritoneal PMIS may follow an indolent course for many years and prompts the question whether these tumors should uniformly be treated aggressively.

Keywords: BRCA1-associated protein 1; Malignant mesothelioma in situ; Papillary mesothelioma in situ; Peritoneum; Well-differentiated papillary mesothelial tumor

DOI: https://doi.org/10.1007/s00428-023-03593-8