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Jennifer Rubin Grandis, M.D.

Jennifer Rubin Grandis, M.D.
Biography

University of Pittsburgh Schools of the Health Sciences

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​New Biological Markers Accurately Predict Prognosis In Head And Neck Cancer Patients, Find University Of Pittsburgh Cancer Institute Researchers

PITTSBURGH, June 11, 1998 — 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 a scientific article published in the June 3 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 cervical lymph node dissection (removal of lymph nodes from the neck), the traditional staging method. The UPCI report also bolsters the theory that blocking overproduction of these two proteins might 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. Moreover, until now, no substantial support existed that levels of these proteins rival other traditional methods of measuring disease progression, such as regional lymph node staging or evaluating tumor size.

"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, M.D., principal investigator on the study, director of the Head and Neck Cancer Program at the 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," she added.

The UPCI investigators have designed an anti-cancer 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 (sequences of genetic material) 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 "anti-sense" therapy effectively inhibited tumor growth and resulted in cancer cell death, or apoptosis. This research, which provides the basis for clinical testing of these anti-sense agents, was reported by Dr. Rubin Grandis and her colleagues at the annual meeting of the American Association of Cancer Research this 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, M.D., co-investigator on 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 a widely available and highly sensitive technology, 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 subjected to computerized image analysis, which quantifies the levels of these proteins in the tissue samples by registering the intensity of the staining.

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.

Researchers at UPCI are at the forefront of experimental work in developing molecular diagnostic methods for detecting cancer and in developing novel cancer treatments. As one of a select group of National Cancer Institute-designated comprehensive cancer centers, UPCI is recognized for its interdisciplinary approach to cancer prevention, detection, diagnosis, treatment, education and community outreach and for its commitment to translational research that brings new cancer therapies from the laboratory bench to the patient’s bedside as rapidly as possible.

For additional information about the UPCI, please visit the UPMC Cancer Center website.

 

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