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| Item Type: | Article |
|---|---|
| Title: | Targeting claudin-overexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin |
| Creators Name: | Piontek, A. and Eichner, M. and Zwanziger, D. and Beier, L.S. and Protze, J. and Walther, W. and Theurer, S. and Schmid, K.W. and Führer-Sakel, D. and Piontek, J. and Krause, G. |
| 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. |
| Keywords: | Clostridium perfringens Enterotoxin, Claudins, Thyroid Cancer, Lung Cancer, Directed Mutagenesis, Necrosis, Animals, Mice |
| Source: | Molecular Oncology |
| ISSN: | 1574-7891 |
| Publisher: | Wiley |
| Volume: | 14 |
| Number: | 2 |
| Page Range: | 261-276 |
| Date: | February 2020 |
| Official Publication: | https://doi.org/10.1002/1878-0261.12615 |
| PubMed: | View item in PubMed |
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