Mesothelin (MSLN)
A protein normally found only on the thin lining of the chest and abdomen, but made in large amounts by mesothelioma and by most pancreatic and many ovarian cancers. Because healthy organs barely make it, it is an attractive handle for antibody-based imaging and treatment.
Overview
Mesothelin is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein whose normal expression is restricted to mesothelial cells lining the pleura, pericardium and peritoneum. Its physiological function is not fully established, but it binds CA-125/MUC16, an interaction implicated in the peritoneal spread of ovarian cancer, and its overexpression has been linked to activation of NF-κB, MAPK and PI3K signalling that promotes proliferation, invasion and resistance to apoptosis.
Mesothelin is essentially absent from normal pancreas but is expressed in close to 100% of pancreatic ductal adenocarcinomas and virtually all epithelioid (though not sarcomatoid) mesotheliomas, and in a substantial majority of ovarian carcinomas (particularly serous subtype) and roughly half of lung adenocarcinomas, giving a wide tumour-to-normal-tissue contrast that has made it a target for antibody-drug conjugates (for example DMOT4039A/anetumab), immunotoxins (SS1P, LMB-100), CAR-T therapy and radiolabelled antibodies. 89Zr-labelled anti-mesothelin antibody immunoPET (for example 89Zr-MMOT0530A) has visualised pancreatic and ovarian cancer lesions in patients, with higher mean tumour SUVmax in ovarian than pancreatic lesions, plausibly reflecting the dense desmoplastic stroma that limits antibody penetration in pancreatic tumours. A thorium-227-labelled anti-mesothelin antibody-chelator conjugate (BAY2287411) has been tested in a first-in-human alpha-therapy trial in mesothelin-expressing tumours.
As a target, mesothelin's strength is a genuinely restricted normal-tissue expression pattern combined with near-universal expression in several hard-to-treat cancers. Its main limitations are that, as an antibody target, achieving good tumour penetration in stroma-rich tumours such as pancreatic adenocarcinoma is harder than in mesothelioma or ovarian cancer, and mesothelin is also shed from the cell surface into blood and ascites, which can act as an antigen sink for circulating antibody-based agents.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · A protein normally found only on the thin lining of the chest and abdomen, but made in large amounts by mesothelioma and by most pancreatic and many ovarian cancers. Because healthy organs barely make it, it is an attractive handle for antibody-based imaging and treatment.
- 1 · What it is
A protein normally found only on the thin lining of the chest and abdomen, but made in large amounts by mesothelioma and by most pancreatic and many ovarian cancers. Because healthy organs barely make it, it is an attractive handle for antibody-based imaging and treatment.
- 2 · What goes wrong in cancer
A GPI-anchored cell-surface glycoprotein normally restricted to mesothelial cells lining the pleura, pericardium and peritoneum, whose interaction with CA-125/MUC16 has been implicated in the peritoneal spread of ovarian cancer.
- 3 · How drugs use it
No product in this corpus aims at Mesothelin (MSLN) yet. Because it sits on the outside of the cell, it can be reached from the bloodstream: antibodies flag the cell, ADCs deliver a toxin, radioligands deliver radiation, and CAR-T or bispecifics bring a T cell.
External identifiers
Biology
A GPI-anchored cell-surface glycoprotein normally restricted to mesothelial cells lining the pleura, pericardium and peritoneum, whose interaction with CA-125/MUC16 has been implicated in the peritoneal spread of ovarian cancer. It is overexpressed in nearly all pancreatic ductal adenocarcinomas and epithelioid mesotheliomas and in most serous ovarian carcinomas, while normal organ parenchyma is negative.
- Malignant pleural mesothelioma (epithelioid subtype): expressed in essentially all cases, absent in sarcomatoid mesothelioma
- Pancreatic ductal adenocarcinoma: expressed in close to 100% of cases, absent in normal pancreas and chronic pancreatitis
- Ovarian cancer (mainly serous subtype): expressed in roughly 70-100% of cases
- Lung adenocarcinoma: expressed in a substantial minority of cases
- Normal tissue: limited to mesothelial cells of pleura, pericardium and peritoneum
Latest papers
topQuery for this target: (TITLE:"Mesothelin" OR ABSTRACT:"Mesothelin" OR TITLE:"MSLN" OR ABSTRACT:"MSLN") AND (radiopharmaceutical OR radioligand OR radionuclide OR theranostic OR "nuclear medicine" OR "molecular imaging" OR radiotracer OR scintigraphy OR cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Mesothelin (MSLN), not a curated reading list.
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Shares Zirconium-89 and the tag antibody target.