Bacteria that can cause deadly infections in humans
and animals have shown promise in treating cancer by
"eating" tumors from the inside out. Now, two new studies
at the
Johns Hopkins Kimmel Cancer Center have demonstrated
that, combined with specially packaged anti-cancer drugs,
the bacterial therapy's prospects for cancer eradication
have dramatically improved.
In mouse experiments reported in the Nov. 24 issue of
Science, the Johns Hopkins researchers demonstrated
that genetically modified bacteria called Clostridium
novyi-NT have a special taste for oxygen-starved
environments much like those found in the core of cancer
cell clusters. The modified bacteria themselves are
relatively harmless, but their unmodified counterparts
produce poisons that have killed some humans and cattle
when introduced into the bloodstream.
"It is not difficult to kill cancer cells. The
challenge is killing them while sparing normal cells," said
Bert Vogelstein, professor and co-director of the Ludwig
Center and Howard Hughes Medical Institute at the Johns
Hopkins Kimmel Cancer Center and one of the study's senior
authors.
The bacteria's cancer-killing effects were first
discovered five years ago by the Vogelstein-led team, who
noticed the germ's ability to grow and spread in the
oxygen-poor core of mouse tumors and the blackened scars
signaling that most of the cancer cells had been destroyed.
Normal surrounding cells were largely unaffected. But the
bacteria failed to kill cancer cells at the still
oxygen-rich edge of the tumors.
In response, the Johns Hopkins researchers added
specially packaged chemotherapy to the bacterial attack,
speculating that certain properties of the bacteria would
improve the drug's effectiveness, said Shibin Zhou,
assistant professor of oncology at the Johns Hopkins Kimmel
Cancer Center.
The combo approach temporarily wiped out both large
and small tumors in almost 100 mice and permanently cured
more than two-thirds of them.
The likely explanation for the greater cancer cell
kill by the combination treatment is that the bacteria
expose the tumors to six times the amount of chemotherapy
than is usually the case by improving the breakdown and
dispersal of the chemotherapy's fatty package at the tumor
site.
The investigators repeated experiments using two
packaged chemotherapy drugs — doxorubicin and
irinotecan — and observed similar tumor-killing
effects of both when used in combination with the bacteria.
"Packaged" cancer drugs currently are available in
microscopic fatty capsules called liposomes that gravitate
to tumors because they are too large to fit through the
skins of tightly woven blood vessels surrounding normal
tissue and small enough to get through tumor vasculature.
Combining C.novyi-NT and liposomes filled with
chemotherapy seems to have its synergistic effect on tumors
owing to the presence of an enzyme found lurking in
C.novyi-NT cultures that Ian Cheong, in the Vogelstein lab,
dubbed liposomase. It destroys fatty membranes and may
disrupt the outer layer of liposomes releasing their drug
contents.
"Drugs contained in these 'Trojan horse' compartments
are specifically released at the tumor site by the
C.novyi-NT bacteria, which may improve the effectiveness
and safety of the therapy," said Cheong, who is the lead
author of the study.
The scientists note that liposomase could be used in a
variety of other targeted therapies besides the bacteria
combination. Such approaches could include attaching
liposomase to antibodies that have an affinity for specific
tumors or adding its DNA code to gene therapy. As many
drugs can be packaged within liposomes, the investigators
say the approach could have general utility.
In a companion study published in the Nov. 19 online
issue of Nature Biotechnology, the Johns Hopkins team
decoded the entire C.novyi-NT genome, a step that Zhou said
"was instrumental in identifying liposomase and will help
improve our bacterial-based therapies."
Preliminary safety tests of injected C.novyi-NT alone
are under way in a small number of cancer patients.
The research was funded the Virginia and D.K. Ludwig
Fund for Cancer Research, the Commonwealth Foundation, the
Miracle Foundation and the National Institutes of
Health.
Co-authors are Xin Huang, Chetan Bettegowda, Luis A.
Diaz Jr. and Kenneth W. Kinzler, all of the Johns Hopkins
Kimmel Cancer Center.
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