Findings that tissue levels of two proteins
correlate closely with the prognosis of head and neck cancer may
significantly alter the detection, staging, and treatment of this
disease, according to an article published in the June 3rd issue of
the Journal of the National Cancer Institute.
The preliminary study, reported by researchers at the University of
Pittsburgh Cancer Institute (UPCI), focuses on two proteins that
accelerate the growth of cancer cells and now appear to predict
clinical outcome as accurately as does cervical lymph node
dissection, the traditional staging method. The UPCI report also
bolsters the theory that blocking overproduction of these two
proteins may effectively cure head and neck cancer.
The marker proteins, transforming growth factor-alpha (TGF-alpha) and
its receptor, epidermal growth factor receptor (EGFR), are known to
be overproduced in some cancers, including breast, lung, and ovarian
carcinoma. Higher levels of these two proteins correlate with a worse
prognosis; correspondingly, lower levels correlate with longer life
expectancy. Previous scientific reports have found that TGF-alpha and
EGFR are not expressed uniformly within a specific type of cancer.
Until now, moreover, no substantial evidence indicated that levels of
these proteins rival other traditional methods of measuring disease
progression, such as regional lymph node staging or evaluation of
"Ours is the first report which finds that measuring levels of
these proteins is as accurate as removing lymph nodes to measure
disease progression and predict patient outcome," said Jennifer
Rubin Grandis, MD, principal investigator of the study, director of
the Head and Neck Cancer Program at UPCI, and assistant professor of
otolaryngology at the University of Pittsburgh School of Medicine.
"In our report, all patients with head and neck cancer have
elevated protein expression of TGF-alpha and EGFR. Our previous
studies indicate that people without this disease produce low levels
of TGF-alpha and very little, if any, EGFR, in the head and neck
tissues," added Dr. Rubin Grandis."Our findings have
enormous potential. We could use this information to identify
patients at high risk for recurrent disease and develop a targeted
therapy based on the biology of these markers."
"Blocking overproduction of TGF-alpha and EGFR may decrease
cancer progression in patients with head and neck tumors. Already, we
have shown this to be the case in laboratory animals, and we are
currently designing a clinical trial for patients with head and neck
cancer based on the extremely encouraging results we have seen in
these studies," Dr. Rubin Grandis noted.
The UPCI investigators have designed an anticancer strategy based on
the biology of TGF-alpha and EGFR. Within tissues, TGF-alpha binds to
EGFR, causing cell proliferation. Both proteins are produced in
abnormally high levels in tumor cells, suggesting that they play an
important role in maintaining cancer growth.
In recent research, UPCI investigators created gene therapy
constructs that block the expression of TGF-alpha and EGFR proteins.
The investigators then injected these agents into human head and neck
tumors growing in laboratory mice. This "antisense" therapy
effectively inhibited tumor growth and resulted in apoptosis. This
research, which provides the basis for clinical testing of these
antisense agents, was reported by Dr. Rubin Grandis and her
colleagues at the annual meeting of the American Association of
Cancer Research this past spring.
"The levels of these two proteins correlate so well with disease
progression that we could potentially use these levels to stage head
and neck cancer patients with much less morbidity than with cervical
lymph node dissection," said David Tweardy, MD, co-investigator
of the study and associate professor in the Departments of Molecular
Genetics and Biochemistry and of Medicine at the University of
Pittsburgh School of Medicine.
"At the present time, we could stratify patients to receive
currently available therapies based on how aggressive their disease
appears as indicated by levels of these biological markers," Dr.
Tweardy. "We also have the potential to use these markers to
detect early disease, when it is most easily treated."
To measure tissue levels of TGF-alpha and EGFR, the UPCI research
team took tissue immunohistochemistry and combined it with
computerized image analysis. During this procedure, head and neck
tissues from patients are stained with antibodies that bind to these
proteins. Next, these samples are quantified via computerized image analysis.
Head and neck cancer, which strikes more than 30,000 people in the
United States, is difficult to treat. Risk factors for head and neck
cancer include smoking and alcohol consumption.