Spores of Clostridium engineered for clinical efficacy and safety cause regression and cure of tumors in vivo.

Title: Spores of Clostridium engineered for clinical efficacy and safety cause regression and cure of tumors in vivo.
Author(s): Heap, JT
Theys, J
Ehsaan, M
Kubiak, AM
Dubois, L
Paesmans, K
Mellaert, LV
Knox, R
Kuehne, SA
Lambin, P
Minton, NP
Item Type: Journal Article
Abstract: Spores of some species of the strictly anaerobic bacteria Clostridium naturally target and partially lyse the hypoxic cores of tumors, which tend to be refractory to conventional therapies. The anti-tumor effect can be augmented by engineering strains to convert a non-toxic prodrug into a cytotoxic drug specifically at the tumor site by expressing a prodrug-converting enzyme (PCE). Safe doses of the favored prodrug CB1954 lead to peak concentrations of 6.3 μM in patient sera, but at these concentration(s) known nitroreductase (NTR) PCEs for this prodrug show low activity. Furthermore, efficacious and safe Clostridium strains that stably express a PCE have not been reported. Here we identify a novel nitroreductase from Neisseria meningitidis, NmeNTR, which is able to activate CB1954 at clinically-achievable serum concentrations. An NmeNTR expression cassette, which does not contain an antibiotic resistance marker, was stably localized to the chromosome of Clostridium sporogenes using a new integration method, and the strain was disabled for safety and containment by making it a uracil auxotroph. The efficacy of Clostridium-Directed Enzyme Prodrug Therapy (CDEPT) using this system was demonstrated in a mouse xenograft model of human colon carcinoma. Substantial tumor suppression was achieved, and several animals were cured. These encouraging data suggest that the novel enzyme and strain engineering approach represent a promising platform for the clinical development of CDEPT.
Publication Date: 15-Apr-2014
URI: http://hdl.handle.net/10044/1/21460
ISSN: 1949-2553
Publisher: Impact Journals
Start Page: 1761
End Page: 1769
Journal / Book Title: Oncotarget
Volume: 5
Issue: 7
Copyright Statement: © 2014 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Conference Place: United States
Appears in Collections:Faculty of Natural Sciences



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