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Targeting claudin-overexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin

Authors

  • A. Piontek
  • M. Eichner
  • D. Zwanziger
  • L.S. Beier
  • J. Protze
  • W. Walther
  • S. Theurer
  • K.W. Schmid
  • D. Führer-Sakel
  • J. Piontek
  • G. Krause

Journal

  • Molecular Oncology

Citation

  • Mol Oncol 14 (2): 261-276

Abstract

  • Clostridium perfringens enterotoxin (CPE) can be used to eliminate carcinoma cells that overexpress on their cell surface CPE receptors - a subset of claudins (e.g. Cldn3 and Cldn4). However, CPE cannot target tumors expressing solely CPE-insensitive claudins (such as Cldn1 and Cldn5). To overcome this limitation, structure-guided modifications were used to generate CPE variants that can strongly bind to Cldn1, Cldn2 and/or Cldn5, while maintaining the ability to bind Cldn3 and Cldn4. This enabled (i) targeting of the most frequent endocrine malignancy, namely, Cldn1-overexpressing thyroid cancer, and (ii) improved targeting of the most common cancer type worldwide, non-small cell lung cancer (NSCLC), which is characterized by high expression of several claudins, including Cldn1 and Cldn5. Different CPE variants, including the novel mutant CPE-Mut3 (S231R/S313H), were applied on thyroid cancer (K1 cells) and NSCLC (PC-9 cells) models. In vitro, CPE-Mut3, but not CPEwt, showed Cldn1-dependent binding and cytotoxicity towards K1 cells. For PC-9 cells, CPE-Mut3 improved claudin-dependent cytotoxic targeting, when compared to CPEwt.In vivo, intratumoral injection of CPE-Mut3 in xenograft models bearing K1 or PC-9 tumors induced necrosis and reduced the growth of both tumor types. Thus, directed modification of CPE enables eradication of tumor entities that cannot be targeted by CPEwt, for instance Cldn1-overexpressing thyroid cancer by using the novel CPE-Mut3.


DOI

doi:10.1002/1878-0261.12615