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Review
. 2021 Aug 4;13(16):3932.
doi: 10.3390/cancers13163932.

Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Dannel Yeo  1   2   3 , Laura Castelletti  1   2   3 , Nico van Zandwijk  2   3   4 , John E J Rasko  1   2   3   5
Affiliations
Review

Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma

Dannel Yeo et al. Cancers (Basel). .

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

Keywords: CAR T cells; biomarker; cancer; immunotherapy; malignant mesothelioma; malignant pleural mesothelioma; mesothelin; therapeutic target.

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Conflict of interest statement

D.Y., L.C. and N.v.Z. declare no conflict of interests. J.E.J.R. reports advisory roles in Gene Technology Technical Advisory, Office of the Gene Technology Regulator, and Australian Government. J.E.J.R. also reports honoraria speaker fees or advisory roles for GSK, Takeda, Gilead, Cynata, Pfizer, Spark, Novartis, Celgene, bluebird bio, Shire, Avrobio; stocks in Genea; and consultant roles for Rarecyte (stocks in lieu) and Imago.

Figures

Figure 1
Figure 1
Hitting the bull’s-eye. (A) Structural characteristics of mesothelin (MSLN). The MSLN precursor protein (precursor MSLN) at the cell surface is cleaved by furin to release soluble megakaryocyte potentiating factor (MPF), leaving MSLN in its mature form (mature MSLN). Mature MSLN can be shed from the cell membrane by the ADAM17 converting enzyme to form soluble mesothelin-related peptide (SMRP). MPF and SMRP have both been detected in the blood and pleural fluid of MPM patients. MUC16 (or CA125) cells binds to MSLN on tumor for adhesion and to promote cancer metastasis. (B) Approaches targeting MSLN used in MPM clinical trials. Several MSLN-targeted therapies have emerged: the chimeric monoclonal antibody MORAb-009; the antibody–drug conjugates anetumab ravtansine, BMS-986148, and BAY2287411; the immunotoxins SS1P and LMB-100; the cancer vaccine CRS-207; and chimeric antigen receptor (CAR) T cell therapy.
See this image and copyright information in PMC

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