Modulating mesothelin shedding to improve therapy

Our plain-English summary of Modulating mesothelin shedding to improve therapy, by I. Pastan, Y. Zhang (Oncotarget, 2012).

The study

• Authors: I. Pastan, Y. Zhang
• Journal: Oncotarget
• Published: 2012;3(2):114-5
• Type of article: Editorial
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

In plain English

This two-page commentary described the authors' own laboratory work on mesothelin, a protein found in large amounts on many tumors, including mesothelioma, and shed from the cell surface. It described the experiments only in general terms, without detailed methods or numbers; the underlying study was published elsewhere. The authors' lab had designed SS1P, a drug that binds mesothelin and carries a bacterial toxin into the cell. Working with a laboratory cell line called A431/H9, the authors reported that several phospholipase inhibitors failed to reduce shedding. Broad-spectrum MMP/ADAM enzyme inhibitors did reduce it, and so did lowering the enzyme TACE (ADAM17). When TACE was lowered or blocked in cultured cells, SS1P was more toxic to the cells, and the cells had more surface mesothelin and took up SS1P faster. TACE inhibition also made other mesothelin-expressing cell lines, and mesothelioma cells from several patients, more sensitive to SS1P. The authors noted that their laboratory test did not account for how the drug behaves throughout the body. They also noted that no effective ADAM17 inhibitor was available for clinical studies. The article did not discuss asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Short commentary (research perspective) summarizing the authors' own previously published laboratory (in vitro) studies. Experiments are described in general terms, without a detailed methods section or numerical data.
• Who was studied: Cultured cells: mainly the A431/H9 cell line, plus other mesothelin-expressing cell lines and primary mesothelioma cells from several patients (numbers not given)
• Exposure: No asbestos exposure was studied. The cells were treated with the mesothelin-targeted immunotoxin SS1P. TACE (ADAM17) was reduced by siRNA or blocked with small inhibitor molecules. Phospholipase inhibitors and broad-spectrum MMP/ADAM inhibitors were also tested.
• Main results:
  • In A431/H9 cells, phospholipase did not appear to play a significant role in mesothelin shedding: several phospholipase inhibitors failed to reduce it
  • Broad-spectrum MMP/ADAM inhibitors significantly inhibited mesothelin shedding
  • Reducing TACE with siRNA significantly reduced mesothelin shedding
  • In cultured cells, SS1P was more toxic when TACE was knocked down or inhibited. The cells showed higher surface mesothelin levels and faster internalization of SS1P.
  • TACE inhibition also made other mesothelin-expressing cell lines, and primary mesothelioma cells from several patients, more sensitive to SS1P
• The authors' conclusion: The authors attributed the sensitizing effect to targeting molecules staying bound to mesothelin on the cell surface rather than dissociating. They concluded that understanding how mesothelin levels are modulated will be instrumental to new targeting strategies.
• Limitations the authors state:
  • The in vitro assay did not take into account the possible systemic effects of modulating shedding on drug behavior in the circulation and tumor tissue
  • The authors did not know whether the EGFR pathway played a role in the finding
  • No effective ADAM17 inhibitor was available for clinical studies, and broad-spectrum MMP/ADAM inhibitors had failed in clinical trials
  • Whether other mechanisms, trogocytosis or antigen masking, play a role in mesothelin-targeted therapy had not been evaluated

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin.

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• Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity — B.J. Stish, S. Oh, et al. (2009)
• Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity — R. Mazor, M. Onda, et al. (2016)
• Recombinant Immunotoxin with T-cell Epitope Mutations That Greatly Reduce Immunogenicity for Treatment of Mesothelin-Expressing Tumors — R. Mazor, J. Zhang, et al. (2015)
• Immunogenicity of therapeutic recombinant immunotoxins — R. Mazor, M. Onda, et al. (2016)
• Mesothelin as a target for cervical cancer therapy — K. Jöhrens, L. Lazzerini, et al. (2019)

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