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Modified Clostridium Novyi and the Treatment of Solid Tumours :  Direct
Bacterial Oncolysis and a beacon to the tumor core.

Clostridia have been known
for decades (or longer) to be effective at invading, colonizing

and lysing the hypoxic underperfused
cores of solid tumors. [1]  

Traditional cancer
treatments like chemotherapy and radiotherapy have diminished effectiveness

in the hypoperfused cores of
solid tumors. 
Radiation therapy depends on generation of

oxygen free radicals for much of its effect. [2]  Chemotherapy is
often more effective on rapidly

dividing non-quiescent cells,  and needs to get to the tumor cells to work.

Direct bacterial oncolysis
offers a highly robust approach to destroying tumor
cells. 

C. Novyi was found to be particularly
effective, so a genetically modified version

with no toxin - clostridium novyi NT was developed. [3-4]

C. Novyi NT was quite
effective at lysing tumor core but - since it is a
strict anaerobe –

it spared the well perfused tumor
rim.  This led to a wide variety of
combination treatment

approaches including use of additional chemotherapy and/or  radiotherapy,

RAIT - use of radioimmunoconjugate monoclonal antibodies targeting tumor antigens (CEA),

genetic modification approaches to release prodrug converting enzymes, cytokines,

andlyposomase to more
selectively deliver chemotherapeutic agents encapsulated

inliposomes. [2, 5-7,10-11]

Clostridium Novyi NT
has many advantages (see [10][11] for reviews).  One of clostridium

novyi NT's main advantages is its high tumor
specificity –  but being a
strict anaerobe –

it leaves the perfused tumor
rim.  Naturally, this suggests the
use of a second lysing bacteria -

an aerobe or a facultative anaerobe to lyse the
rim.  One key problem with this
approach is

that the rim lysing bacteria may not be sufficiently
specific for the tumor tissue and may cause

potentially dangerous systemic infection. 

Ideally, clostridium novyi
NT's remarkable specificity for the tumor core microenvironment

could be used as a beacon
that could subsequently selectively localize other symbiotic

treatment modalities. These modalities would then selectively
target the region proximal

to the modified clostridium novyi NT – the tumor rim - without depending any longer on

direct specificity to the tumor
microenvironment.  For example, rim lysing aerobic or

facultative anaerobic bacteria may be made to be dependent on
local secretion of protective factors

or nutrients from the nearby modified clostridium novyi
NT in the tumor cores.

This may be used to
selectively overcome intentionally designed or selected

auxotrophy / bradytrophy in the rim lysing bacteria.

Alternatively, it may be
use to protect the rim lysing
bacteria from systemic substances that

would otherwise destroy them.  (For example, modified clostridium novyi
NT secreting

beta-lactamase/penicillinase may provide local protection to rim lysing bacteria from systemic

beta lactam antibiotics). Other examples could include :  radioimmunoconjugates

using monoclonal antibodies directed at epitopes on the clostridium
novyi NT

or rim lysing bacteria rather than on specific tumor antigens, and minicells or

liposomes targeted in a
similar manner to deliver chemotherapeutic agents.

Clostridium novyi NT has a promising
future in the ongoing development of

new robust treatments for solid tumors.

References

(1)  The use of clostridial spores for cancer
treatment.

Barbé S, Van Mellaert L, Anné J.

J ApplMicrobiol. 2006 Sep;101(3):571-8. Review.PMID: 16907807

(2)  Overcoming the hypoxic barrier to
radiation therapy with anaerobic bacteria.

Bettegowda C, Dang LH, Abrams R, Huso
DL, Dillehay L, Cheong I, Agrawal
N, Borzillary S,

McCaffery JM, Watson EL, Lin KS, Bunz
F, Baidoo K, Pomper MG, Kinzler KW, Vogelstein B, Zhou S.

Proc NatlAcadSci U S A. 2003 Dec 9;100(25):15083-8. Epub 2003 Dec
1.PMID: 14657371

(3)  Combination bacteriolytic therapy for
the treatment of experimental tumors.

Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B.

Proc NatlAcadSci U S A. 2001 Dec 18;98(26):15155-60. Epub 2001 Nov
27.PMID: 11724950

(4)  Bacteriolytic therapy can generate a
potent immune response

against experimental tumors. 

Agrawal N, Bettegowda C, Cheong I, Geschwind JF, Drake CG, Hipkiss
EL, Tatsumi M, Dang LH, Diaz LA Jr,
Pomper M, Abusedera M, Wahl
RL, Kinzler KW, Zhou S, Huso
DL, Vogelstein B.

Proc NatlAcadSci U S A. 2004 Oct 19;101(42):15172-7. Epub 2004 Oct
7.PMID: 15471990

(5)  Targeting cancer with bugs and liposomes: ready, aim, fire.

Cheong
I, Huang X, Thornton
K, Diaz LA Jr, Zhou S.

Cancer Res. 2007 Oct 15;67(20):9605-8. Review. PMID:
17942887

(6)  A bacterial protein enhances the release
and efficacy of liposomal

cancer drugs.

Cheong I, Huang X, Bettegowda C, Diaz LA Jr, Kinzler KW, Zhou S, Vogelstein B.

Science. 2006 Nov 24;314(5803):1308-11.
PMID: 17124324

(7)  Optimized clostridium-directed enzyme prodrug therapy improves the antitumor activity of the
novel DNA cross-linking agent PR-104. 

Liu SC, Ahn
GO, Kioi M, Dorie MJ, Patterson
AV, Brown JM.

Cancer Res. 2008 Oct 1;68(19):7995-8003.PMID: 18829557

(8)  Containment of tumor-colonizing
bacteria by host neutrophils.

Westphal K, Leschner S, Jablonska J, Loessner H, Weiss S.

Cancer Res. 2008 Apr 15;68(8):2952-60.PMID: 18413765

(9)  Targeted therapy with a Salmonella typhimurium
leucine-arginine auxotroph

cures orthotopic human breast tumors
in nude mice.

Zhao M, Yang M, Ma H, Li X,
Tan X, Li S, Yang Z, Hoffman RM.

Cancer Res. 2006 Aug 1;66(15):7647-52.PMID: 16885365

(10) Bacterial therapies:
completing the cancer treatment toolbox.

St Jean AT, Zhang M, Forbes
NS.

CurrOpinBiotechnol. 2008 Oct;19(5):511-7. Epub 2008 Sep 18.

Review.  PMID:
18760353

(11)  Clostridial spores as live 'Trojan
horse' vectors for cancer gene therapy: comparison with viral delivery systems.

Wei MQ, Ren R, Good D, Anné J.  Genet Vaccines Ther. 2008 Feb 17;6:8.PMID: 18279524