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| Item Type: | Article |
|---|---|
| Title: | Effective oncoleaking treatment of pancreatic cancer by claudin-targeted suicide gene therapy with Clostridium perfringens enterotoxin (CPE) |
| Creators Name: | Pahle, J., Kobelt, D., Aumann, J., Behrens, D., Daberkow, O., Mokritzkij, M., Piontek, J., Stein, U. and Walther, W. |
| Abstract: | Pancreatic cancer (PC) is one of the most lethal cancers worldwide, associated with poor prognosis and restricted therapeutic options. Clostridium perfringens enterotoxin (CPE), is a pore-forming (oncoleaking) toxin, which binds to claudin-3 and-4 (Cldn3/4) causing selective cytotoxicity. Cldn3/4 are highly upregulated in PC and represent an effective target for oncoleaking therapy. We utilized a translation-optimized CPE vector (optCPE) for new suicide approach of PC in vitro and in cell lines (CDX) and patient-derived pancreatic cancer xenografts (PDX) in vivo. The study demonstrates selective toxicity in Cldn3/4 overexpressing PC cells by optCPE gene transfer, mediated by pore formation, activation of apoptotic/necrotic signaling in vitro, induction of necrosis and of bystander tumor cell killing in vivo. The optCPE non-viral intratumoral in vivo jet-injection gene therapy shows targeted antitumoral efficacy in different CDX and PDX PC models, leading to reduced tumor viability and induction of tumor necrosis, which is further enhanced if combined with chemotherapy. This selective oncoleaking suicide gene therapy improves therapeutic efficacy in pancreas carcinoma and will be of value for better local control, particularly of unresectable or therapy refractory PC. |
| Keywords: | Clostridium perfringens Enterotoxin (CPE), Pancreatic Cancer, Gene Therapy, Suicide Gene, Combination Therapy, Animals, Mice |
| Source: | Cancers |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Volume: | 13 |
| Number: | 17 |
| Page Range: | 4393 |
| Date: | 1 September 2021 |
| Official Publication: | https://doi.org/10.3390/cancers13174393 |
| PubMed: | View item in PubMed |
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