Seek and destroy

In Karli Rosner's
revolutionary gene
therapy, cancer
cells are fooled into
killing themselves

compromised, which is true for
many cancer patients.

Patients with the same cancer
type vary in their response to
identical treatment. As a result,
the medical field strives to
develop treatments that can
be adjusted to each patient.
Dr. Rosner's technology is
flexible in that it contains pieces
that together form a genetic
construct. Each piece can be
replaced by one of several other
genetic pieces that perform the
same task, but differ slightly
in their genetics. The multiple
options available for each genetic
piece allow the physician to tailor
the final treatment to the unique
characteristics of a patient's
cancer.

Karli Rosner, M.D., Ph.D., a
physician-researcher at the
Wayne State University School
of Medicine, has developed
a unique therapy to treat
a wide range of cancers.
The treatment is based on a
naturally occurring human
enzyme genetically modified
to fool cancer cells into killing
themselves.

The concept, for which Wayne
State has applied for patent
protection, was demonstrated
on melanoma cells that are
resistant to routine treatments
such as chemotherapy or
radiotherapy. Melanoma is a
perfect model for testing this
new therapy; it is considered
the most aggressive form of
human cancer because of its
many defense mechanisms
against available treatments.
The therapy's success in killing
melanoma suggests a similar
outcome in treating other
cancers.

Dr. Rosner is assistant professor
and director of research in the
Department of Dermatology.
His method uses genetic
constructs that contain a
genetically modified enzyme —
DNase1 protein — to seek out
and destroy cancer cells.

Dr. Rosner modified —
"hacked," as he puts it — the
genetic code for DNasel,
a potent DNA-degrading
enzyme, and altered its genetic
composition by deleting a part
of the code, mutating another
part and adding an artificial
piece of code. Through these
changes, the altered DNA
program is translated into a
modified protein. In contrast
to the natural protein, the
modified protein will not be
eliminated from the cancer cell,
will resist deactivation by cell
inhibitors and will gain access
to the cell's nucleus.

Karli Rosner, M.D., right, in the lab with research assistant
Evangelia Kirou.

"If you imagine the cell's
nucleus as a computer
and DNA in the nucleus as
computer software," Dr.
Rosner explains, "then the
altered, hacked DNA program
corresponds to a computer
virus."

The cancer cell, unaware of
the destructive potential of
the modified code, translates
it into a protein that evades

The beauty of this therapy
is that specifically targeted
cancer cells destroy themselves,
leaving surrounding healthy
cells intact. This mode of
cancer cell elimination leaves
no residual debris to alert the
immune system to kick in,
essentially committing "the
perfect crime," Dr. Rosner says.

This is important because the
many side effects of current

The beauty of this therapy is
that specifically targeted cancer
cells destroy themselves, leaving
surrounding healthy cells intact.

the cell's defense mechanisms
and enters the nucleus. In the
nucleus, the protein damages
DNA by chopping it into
fragments. Following damage
to DNA, the cell's organelles
disintegrate and the cancer cell
dies. In this way, Dr. Rosner's
technology fools cancer cells
into generating the protein that
will cause their own death.

anti-cancer treatments are
attributed to activation of
the immune system. Not
requiring participation of
the patient's immune system
offers a big advantage over
other technologies such as the
cancer vaccine. Technologies
that depend on the patient's
immune system to destroy
cancer are not effective
if the immune system is

So, in Dr. Rosner's words, the
new technology is a "true
personalized therapy." The
physician exposes a patient's
cancer cells, obtained by
biopsy, to various genetic
constructs to find the version
that kills the patient's cancer
with the utmost efficiency.

This technology has the
potential to treat a variety of
tumors. The destructive genetic
construct can be targeted to
a particular cancer type by
incorporating a genetic piece
that specifically identifies the
cancer. The ability to target the
therapy specifically to cancer
cells will reduce side effects.
Moreover, the ability to target
multiple cancers will immensely
increase the number of patients
that will benefit from this new
technology.

To date, Dr. Rosner has
demonstrated cancer cell kill
rates of 70 to 100 percent
with his first generation of
"gene suicide therapy." To
increase the killing efficiency
even further, he has designed
a second generation of
constructs. He plans to test the
therapy in an animal model,
an intermediate step required
before moving the treatment
into clinical trial.

To read the complete study,
visit http.//www.nature.com
cgt/jou mal/vaopin current/
fullicgt201 084a. html.

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