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Cytotoxic Activity of Immunotoxin SS1P Is Modulated by TACE-Dependent Mesothelin Shedding

  1. Author:
    Zhang, Y. J.
    Chertov, O.
    Zhang, J. L.
    Hassan, R.
    Pastan, I.

  2. Author Address

    [Zhang, YJ; Zhang, JL; Hassan, R; Pastan, I] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chertov, O] NCI, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA.;Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Rm 5106, Bethesda, MD 20892 USA;pastani@mail.nih.gov
    1. Year: 2011
    2. Date: Sep
  2. Journal: Cancer Research
    1. 71
    2. 17
    3. Pages: 5915-5922
  4. Type of Article: Article
  5. ISSN: 0008-5472
  1. Abstract:

    Mesothelin is a cell-surface tumor-associated antigen expressed in several human cancers. The limited expression of mesothelin on normal tissues and its high expression in many cancers make it an attractive candidate for targeted therapies using monoclonal antibodies, immunoconjugates, and immunotoxins. Mesothelin is actively shed from the cell surface and is present in the serum of patients with malignant mesothelioma, which could negatively affect the response to these therapies. We have found that mesothelin sheddase activity is mediated by a TNF-alpha converting enzyme (TACE), a member of the matrix metalloproteinase/a disintegrin and metalloprotease family. We showed that EGF and TIMP-3 act through TACE as endogenous regulators of mesothelin shedding. We also found that reducing shedding significantly improved the in vitro cytotoxicity of immunotoxin SS1P, which targets mesothelin and is currently in clinical trials for the treatment of patients with mesothelioma and lung cancer. Our findings provide a mechanistic understanding of mesothelin shedding and could help improve mesothelin-based targeted therapies. Cancer Res; 71(17); 5915-22. (C) 2011 AACR.

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External Sources

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  2. DOI: 10.1158/0008-5472.can-11-0466
  3. View record in Web of Science®
  4. WOS: 000294454700032

Library Notes

  1. Fiscal Year: FY2011-2012
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