bims-mesote 2023-06-04 papers

Issue of 2023–06–04
five papers selected by
Laura Mannarino, Humanitas Research

Semin Respir Crit Care Med. 2023 May 30.

New Markers for Management of Mesothelioma.

Alistair Nash, Tina Firth Née Phan, Jenette Creaney.

In this review, we provide an update on the status of cancer biomarkers for the clinical management of pleural mesothelioma, an aggressive cancer associated with asbestos exposure. Mesothelioma can be difficult to diagnose, and response to treatment is transient, even with recently adopted immune checkpoint inhibitor (ICI) combinations. Identification of mesothelioma-specific biomarkers could facilitate early diagnosis and tailor treatment strategies. Mesothelioma is characterized by frequent loss or alteration of the tumor suppressor genes cyclin-dependent kinase inhibitor 2A (CDKN2A) and BRCA1-associated protein-1 (BAP1). Accumulating data show these genes and/or their related protein products will be valuable tissue-based biomarkers for mesothelioma. Loss of BAP1, CDKN2A, p16, or methylthioadenosine phosphorylase provide pathologists with a reliable means of differentiating between mesothelioma and reactive mesothelial cell proliferations. This can aid diagnosis in difficult cases and is requisite for the identification of the new pathological entity malignant mesothelioma in situ. However, limited progress in identifying clinically useful soluble biomarkers in this cancer type has been made, with mesothelin remaining the benchmark. To date, results from studies to identify predictive biomarkers for ICI response have been disappointing. A recent retrospective study demonstrated BAP1 loss was predictive of improved survival following combination pemetrexed- and platinum-based chemotherapy. Validation of this result could have important clinical implications. Clinical trials aimed at targeting therapy based on biomarker expression are generally in the early phase setting, with overall results being moderate. The identification of biomarkers for mesothelioma remains a key research question due to their potential to improve patient outcomes in this deadly cancer.

DOI: https://doi.org/10.1055/s-0043-1769097

Front Oncol. 2023 ;13 1153233

Malignant mediastinal mesothelioma treated with anlotinib: a case report and review of the literature.

Yishi Zhang, Wan He, Ke Zhan, Luobin Zhang, Hua Cao, Ruilian Xu.

Malignant mesothelioma that originates from mediastinal (MMM) is a rare form of malignant pleural mesothelioma (MPM). The prognosis of advanced stage MPM was poor, and the traditional treatment was chemotherapy. Here, we present a patient with MMM that was treated with anlotinib, a multitargeted tyrosine kinase inhibitor (TKI) who had a 24-month progression-free survival (PFS). Further review of the literature showed that, despite some explorations of applying small-molecule multitargeted TKIs in the treatment of MPM, until today, no large series had a positive result. Anlotinib had been approved by the China Food and Drug Administration on treating non-small cell lung cancer, soft tissue sarcoma, renal cell carcinoma, and medullary thyroid cancer. We assumed that the ability of anlotinib to target more tyrosine kinase receptors than most of other TKIs could contribute to the long duration of PFS in this case, but further study is needed to further validate the efficacy of anlotinib in treatment of MPM.

Keywords: anlotinib; malignant mesothelioma; malignant pleural mesothelioma; mediastinal mesothelioma; tyrosine kinase inhibitor

DOI: https://doi.org/10.3389/fonc.2023.1153233

Crit Rev Oncol Hematol. 2023 May 31. pii: S1040-8428(23)00131-2. [Epub ahead of print] 104043

Targeting AXL in Mesothelioma: from functional characterization to clinical implication.

Kinjal Bhadresha, Sheefa Mirza, Clement Penny, Muhammed Jameel Mughal.

Malignant pleural mesothelioma (MM) is a highly aggressive and lethal cancer with a poor survival rate. Current treatment approaches primarily rely on chemotherapy and radiation, but their effectiveness is limited. Consequently, there is an urgent need for alternative treatment strategies, a comprehensive understanding of the molecular mechanisms underlying MM, and the identification of potential therapeutic targets. Extensive studies over the past decade have emphasized the role of Axl in driving tumor development and metastasis, while high levels of Axl expression have been associated with immune evasion, drug resistance, and reduced patient survival in various cancer types. Ongoing clinical trials are investigating the efficacy of Axl inhibitors for different cancers. However, the precise role of Axl in MM progression, development, and metastasis, as well as its regulatory mechanisms within MM, remain inadequately understood. This review aims to comprehensively investigate the involvement of Axl in MM. We discuss Axl role in MM progression, development, and metastasis, along with its specific regulatory mechanisms. Additionally, we examined the Axl associated signaling pathways, the relationship between Axl and immune evasion, and the clinical implications of Axl for MM treatment. Furthermore, we discussed the potential utility of liquid biopsy as a non-invasive diagnostic technique for early detection of Axl in MM. Lastly, we evaluated the potential of a microRNA signature that targets Axl. By consolidating existing knowledge and identifying research gaps, this review contributes to a better understanding of Axl's role in MM and sets the stage for future investigations and the development of effective therapeutic interventions.

Keywords: AXL; Epigenetic; Exosome; Malignant pleural mesothelioma; miRNA

DOI: https://doi.org/10.1016/j.critrevonc.2023.104043

Thorac Cancer. 2023 May 30.

High density and proximity of CD8+ T cells to tumor cells are correlated with better response to nivolumab treatment in metastatic pleural mesothelioma.

BACKGROUND: The efficacy of immune checkpoint inhibitors (ICIs) in pleural mesothelioma has recently been established. The response to ICIs can be predicted by quantitative analysis of cells and their spatial distribution in the tumor microenvironment (TME). However, the detailed composition of the TME in pleural mesothelioma has not been reported. We evaluated the association between the TME and response to ICIs in this cancer.
METHODS: A retrospective analysis of 22 pleural mesothelioma patients treated with nivolumab in different centers was performed using surgical specimens. Four patients had a partial response to nivolumab (response group) and 18 patients had stable or progressive disease (nonresponse group). The number of CD4, CD8, FoxP3, CK, and PD-L1 positive cells, cell density, and cell-to-cell distance were analyzed by multiplex immunofluorescence.
RESULTS: PD-L1 expression did not differ significantly between the response and nonresponse groups. The density of total T cells and of CD8+ T cells was significantly higher in the response than in the nonresponse group. CD8+ T cells were more clustered and located closer to tumor cells, whereas regulatory T cells were located further from tumor cells in the response than in the nonresponse group.
CONCLUSIONS: High density and spatial proximity of CD8+ T cells to tumor cells were associated with better response to nivolumab, whereas the proximity of regulatory T cells to tumor cells was associated with worse response, suggesting that the distinct landscape of the TME could be a potential predictor of ICI efficacy in pleural mesothelioma.

Keywords: immune checkpoint inhibitor (ICI); multiplex immunofluorescence (mIF); nivolumab; pleural mesothelioma; tumor microenvironment (TME)

DOI: https://doi.org/10.1111/1759-7714.14981

BMC Cancer. 2023 May 31. 23(1): 487

Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1.

Fumiya Ito, Katsuhiro Kato, Izumi Yanatori, Yuki Maeda, Toyoaki Murohara, Shinya Toyokuni.

Organoids are a three-dimensional (3D) culture system that simulate actual organs. Therefore, tumor organoids are expected to predict precise response to chemotherapy in patients. However, to date, few studies have studied the drug responses in organoids of malignant mesothelioma (MM). The poor prognosis of MM emphasizes the importance of establishing a protocol for generating MM-organoid for research and clinical use. Here, we established murine MM organoids from p53+/- or wild-type C57BL/6 strain by intraperitoneal injection either with crocidolite or carbon nanotube. Established MM-organoids proliferated in Matrigel as spheroids. Subcutaneous injection assays revealed that the MM-organoids mimicked actual tissue architecture and maintained the original histological features of the primary MM. RNA sequencing and pathway analyses revealed that the significant expressional differences between the 2D- and 3D-culture systems were observed in receptor tyrosine kinases, including IGF1R and EGFR, glycosylation and cholesterol/steroid metabolism. MM-organoids exhibited a more sensitive response to cisplatin through stable plasma membrane localization of a major cisplatin transporter, copper transporter 1/Slc31A1 (Ctr1) in comparison to 2D-cultures, presumably through glycosylation and lipidation. The Matrigel culture system facilitated the localization of CTR1 on the plasma membrane, which simulated the original MMs and the subcutaneous xenografts. These results suggest that the newly developed protocol for MM-organoids is useful to study strategies to overcome chemotherapy resistance to cisplatin.

Keywords: Asbestos; CTR1; Carbon nanotube; EGFR; Mesothelioma; Organoid

DOI: https://doi.org/10.1186/s12885-023-10966-4