Reported by Jennifer Michalowski
February 7, 2002
Proteomics - the study of the proteins inside cells - has made
its way into cancer trials. New technologies that allow researchers
to visualize thousands of proteins at the same time can reveal patterns
that may have important clinical implications.
Proteomic technology will play an important role in two clinical
trials for ovarian cancer sponsored by the National Cancer Institute
(NCI). The first of these trials is an observational study investigating
whether protein patterns can be used to predict recurrence of disease.
A second trial will use proteomics to increase the understanding
of how a cancer drug works.
Proteomics as a tool to detect cancer recurrence
A clinical trial already under way is testing the ability of proteomic
technology to reliably detect relapse of ovarian cancer before clinical
symptoms appear.
"Relapse occurs after first remission in more than 80 percent of
patients with advanced-stage cancer," said Elise Kohn, M.D., Laboratory
of Pathology, NCI, who is the lead investigator on the trial. "A
simple test that identifies the presence of recurrence would be
a valuable clinical tool."
Researchers hope that critical changes due to recurrent cancer
will be reflected in the levels of proteins in cells. In this trial,
they will create profiles of the proteins in blood, urine, and saliva
and look for patterns that indicate ovarian cancer is likely to
return.
Patients whose Stage III or IV epithelial ovarian cancer is in
first clinical remission may enroll in the study within nine weeks
of their final chemotherapy cycle. Trial participants will receive
standard follow-up care for patients with ovarian cancer, including
CT scans and analysis of CA-125 (a blood protein marker) levels,
standard methods of monitoring patients with ovarian cancer.
In addition, researchers will take samples of blood, urine, and
saliva and use them to create protein profiles based on the size
and electrical charge of the proteins in the samples. Samples will
be taken when participants begin the trial, one and three months
later, and again every three months afterward.
Once the profiles have been created, researchers will analyze them
in search of patterns that occur in samples from patients whose
cancer returns, but not in samples from patients whose cancer remains
in remission. They hope such patterns will help clinicians identify
patients whose ovarian cancer is likely to return so that treatment
may begin early.
Proteomics as a tool to understand drug function
Another effort to use proteomics in the clinical setting involves
a trial to monitor tumor cells' protein response to the cancer drug
imatinib mesylate, commonly known as Gleevec. Correlating protein
patterns with clinical outcomes of treatment will allow researchers
to learn more about how the drug works.
The phase II trial, still awaiting final approval but anticipated
to begin soon, will evaluate the effectiveness of Gleevec in treating
ovarian cancer. "From a clinical standpoint, this is a standard
treatment trial," says Kohn. "But we're excited about the unique
opportunity to ask critical questions about how the drug is working
in the patient's tumor."
Gleevec is a molecularly targeted therapy, designed to interfere
with specific molecules that promote cancerous growth. It inhibits
a group of proteins known as tyrosine kinases, which, when not properly
regulated, can play a role in many types of cancer.
Within the last year, the Food and Drug Administration has approved
Gleevec for the treatment of chronic myeloid leukemia, a cancer
of white blood cells, and gastrointestinal stromal tumors. Dozens
of ongoing clinical trials continue to evaluate the role this drug
may play in treating leukemia and other cancers, including glioblastoma
and soft tissue sarcomas, and now ovarian cancer.
This is this first trial to examine Gleevec as a potential therapy
for ovarian cancer. Researchers have found that Gleevec can interfere
with the function of two tyrosine kinases that may be important
in ovarian cancer, c-kit and the PDGF (platelet-derived growth factor)
receptor, suggesting that Gleevec may be an effective therapy for
patients with ovarian cancer.
To determine whether Gleevec affects the predicted pathways in
cancer cells, biopsies of patients' tumors will be taken prior to
and after one month of treatment. From the biopsied tissue, researchers
will analyze the quantity and activity of proteins in the cancerous
cells. For this trial, researchers will use microarrays, a proteomics
tool that will allow them to focus on a set of critical proteins
they expect the drug to affect.
Patients will continue receiving treatment and their clinical response
to the drug will be correlated with protein changes observed, providing
researchers with a better understanding of the specific ways Gleevec
affects tumor cells. This knowledge will be important to scientists
as they look for ways to improve the drug.
"For any molecularly targeted drug, you really want to know how
it's working or why it doesn't," said Kohn. "This technology provides
a way to ask those questions in patients that are actually receiving
the drug."
Interested patients can call NCI's Clinical Studies Support Center
at (888) 624-1937 to learn more about both trials.
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