Gene Silencing
and Imaging Form Basis of Research for Early Chemotherapy
Response
May / June 2005
Molecular beacons, gene silencing and innovative imaging
techniques aimed at expanding the oncology patient's
most limited resource -- time -- are being researched
at the Abramson Cancer Center of the University of Pennsylvania.
The pre-clinical studies were created to forecast early response
to chemotherapy to adjust treatment choices.
“Those
of us who have treated terminally ill patients know that
these people often don't have a lot of time to wait
and find out if a specific treatment is working,” says
Wafik
El-Deiry, MD, PhD, associate professor, Departments
of Medicine, Genetics, and Pharmacology. “If we have
a good indication that a tumor is responding to treatment,
then we’re essentially buying time to be able to continue
with the same treatment or to try something else.”
Dr. El-Deiry and his research team are working to develop
new ways of determining whether patients are responding to
chemotherapy by imaging molecular events that can both predict
response or those that correlate with response to therapy. “These
molecular events involve changes in expression of genes that
are activated when patients receive chemotherapy and also
include detecting the death of tumor cells in advance. Both
of these types of events should be possible to image,” he
says.
To achieve this, Dr. El-Deiry is using molecular ‘beacons,’ which
are cellular molecules that are activated by their response
to chemotherapy. When the ‘beacon’ recognizes
a characteristic change in chemo-treated tumor cells it becomes
illuminated. Strong fluorescence equals a good response to
the chemotherapy. Dr. El-Deiry hopes to develop a scan --
similar to a positron emission tomography (PET) scan -- based
on this model.
Much of this research is built on gene silencing. “We
have to understand apoptosis and the genes that are turned
on in cell death to even begin to develop the types of tests
that we’re exploring,” says Dr. El-Deiry. “Gene
silencing provides a genetic tool to eliminate the expression
of a specific gene that one might think is involved in the
response to chemotherapy or which is involved in cell death.
Then, one can look directly at tumor cells or tumor masses
in mice and visualize the effect of eliminating such a gene.
These pre-clinical studies determine which genes are relevant
to tumor growth and tumor response to therapy and form the
basis for which genes we should image.”
Today, with the exception of cancers for which tumor markers
exist, there are no reliable ways of predicting who will
respond to chemotherapy,” Dr. El-Deiry said. Ovarian
and testicular cancer tumors are examples of tumors that
currently have markers. “If the patient’s carcinoembryonic
antigen (CEA) or Alpha-feta protein (AFP) or CA 125 level
drops, we know the tumor is shrinking,” he says. “But
for many other tumors, including some of the most common,
such as colon, lung and breast cancers, we don’t have
any serum markers that can be used to monitor response in
the period right after therapy.”
Patients who will benefit most from this research are those
who do not respond to the first line of treatment. “We
often have to give two or three cycles of chemotherapy before
we have any idea if it’s having an effect,” Dr.
El-Deiry says. “If we had a way of knowing early on
that a patient definitely wasn’t responding to a treatment,
then we wouldn’t give them the next cycle. We might
have more remaining time to try something else.”
Under ideal circumstances, a molecular imaging scan that
can predict early response to chemotherapy could be in clinical
trials within three years, according to Dr. El-Deiry.
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