Journal of Stem Cell Research & Therapy

Clostridium perfringens enterotoxin mediated suicidal gene therapy for pancreatic cancer

4^th International Conference and Exhibition on Cell & Gene Therapy

August 10-12, 2015 London, UK

Jessica Pahle1, Diana Behrens2, Ole Daberkow2, Jutta Aumann1, Dennis Kobelt3 and Wolfgang Walther1,3

Scientific Tracks Abstracts: J Stem Cell Res Ther

Abstract:

Bacterial toxins have evolved to an effective therapeutic option for cancer therapy and numerous studies demonstrated
their antitumoral potential. The Clostridium perfringens Enterotoxin (CPE), produced by the anaerobic Clostridium
perfringes bacteria is a pore forming toxin with a selective, receptor-dependent cytotoxicity. The transmembrane tight junction
proteins claudin-3 and claudin-4 are known high-affine CPE receptors and are highly upregulated in several human epithelial
cancers such as breast, colon, ovarian and pancreatic cancer. CPE binding to its receptor triggers membrane pore complex
formation which leads to rapid cell death. Here we aimed at evaluation of an efficient eradication of claudin-3 and or claudin-4
overexpressing pancreatic cancer by using a non-viral translation optimized CPE vector (optCPE) in vitro and in vivo. In this
study we investigated the sensitivity of human pancreatic cancer cell lines and more interestingly patient derived pancreatic
cancer xenograft (PDX) derived cells for treatment with recombinant CPE (recCPE) as well as by optCPE gene transfer.
Claudin-3 and or -4 overexpressing cancer cells revealed high sensitivity towards both recCPE treatment and optCPE gene
transfer. Particularly for optCPE toxicity up to 100% was observed 72 hours after gene transfer. We also demonstrated a positive
correlation between cytotoxic activity of CPE and level of claudin expression. The optCPE gene transfer led to rapid cytotoxic
effects such as massive membrane disruption, cell as well as nuclear disintegration selectively in claudin overexpressing cells.
This supports the targeted CPE toxicity which eradicates claudin-3 and or -4 overexpressing pancreatic cancer. The non-viral
intratumoral in vivo gene transfer of optCPE led to reduced tumor viability in cell line xenotransplant and PDX bearing mice
compared to the control group. This study emphazies the great potential of this novel selective CPE mediated suicidal gene
therapy of claudin-3 and or -4 overexpressing pancreatic tumors.