"Head and neck cancer is one of the most physically and emotionally debilitating cancers," said Jennifer Grandis, M.D., principal investigator of the grant and professor of otolaryngology and pharmacology, University of Pittsburgh School of Medicine, and director of UPCI's Head and Neck Cancer Program. "Treatment options are limited and often leave a patient with disabling side effects that can have a devastating impact on quality of life. This grant will enable us to enhance the quality of life for head and neck cancer patients and greatly improve their prognoses through the collaborative efforts of our researchers in the laboratory and clinic."
The grant funds four major translational research projects that focus on genetic changes that are potential risk factors for head and neck cancer, intracellular signaling proteins activated during head and neck cancer, and new treatment strategies designed to reduce the morbidity and mortality from head and neck cancer.
According to Dr. Grandis, each project within the grant has two co-leaders, one with expertise in basic or laboratory science and the other with expertise in clinical research and care. By integrating laboratory findings with clinical research and epidemiological data, Dr. Grandis expects study results to be more rapidly disseminated to cancer patients. The grant also includes input from patient advocates who will focus on research-related patient issues and act as a liaison between patients and scientists.
In the first major project in the grant, Marjorie Romkes, Ph.D., associate professor, center for clinical pharmacology, department of medicine, and Joel Weissfeld, M.D., M.P.H., associate professor, department of epidemiology, will examine the correlation between promising genetic markers for head and neck cancer and tobacco and alcohol use.
"Eighty percent of head and neck cancer patients are smokers, chew tobacco and consume large amounts of alcohol," said Dr. Romkes. "If we can determine who among this population will most likely develop cancer, we can screen and treat them earlier, potentially improving their prognoses and quality of life."
To better identify these individuals, Drs. Romkes and Weissfeld will examine alterations in a DNA repair gene, XPD, and a cell cycle regulatory gene, cyclin D1, that previous research at UPCI has determined are significant predictors of head and neck cancer risk, as well as increased risk for lung cancer in smokers. The researchers will examine the interaction of these genes with the goal of identifying individuals who have an increased likelihood of developing head and neck cancer.
In another project, Dr. Grandis and Daniel Johnson, Ph.D., associate professor of medicine, will examine intracellular signaling proteins called Signal Transducer and Activators of Transcription (STATs) that have been linked to tumor progression in several cancers, including head and neck cancer. These proteins represent a critical survival pathway in head and neck cancer because they activate a protein, BCL-X, that interferes with apoptosis, or cell death. By targeting STAT signaling, the researchers hope to inhibit the progression of head and neck cancer.
Albert DeLeo, Ph.D., professor of pathology, and Robert Ferris, M.D., Ph.D., assistant professor of otolaryngology, will head up an additional project to develop a therapeutic vaccine that targets the tumor-suppressing gene p53. A critical gene involved in the development of many cancers, p53 is damaged in most cancers and this damage is correlated with worse clinical outcomes. Previous research has indicated that mutant p53 also expresses non-mutant p53 peptides in tumors. When combined with dendritic cells, these p53 peptides may induce an immune response, decreasing the chance of cancer recurrence and the formation of secondary tumors.
In a final project, Jill Siegfried, Ph.D., professor of pharmacology, and Dr. Grandis will examine multiple signaling pathways implicated in the proliferation of head and neck cancer.
"Unfortunately, head and neck cancer tumors are challenging to treat because they develop strategies to escape the anti-tumor effects of most therapies," said Dr. Siegfried. "One way to address this difficulty is to develop therapeutic approaches that target multiple signaling pathways."
Drs. Siegfried and Grandis are examining the interaction of two types of protein receptors implicated in the proliferation of head and neck cancer, epidermal growth factor receptor (EGFR) and members of the G-protein-coupled receptor (GPCR) family. While both types are over-expressed in head and neck cancer, preliminary studies suggest that combining strategies that block both receptor families has a synergistic effect on inhibiting the growth of head and neck cancer cells.
With 36,200 estimated new cases and 11,000 deaths in 2003, head and neck cancer accounts for 4 percent to 5 percent of all newly diagnosed cancers in the United States. More than two-thirds of head and neck cancer patients have a locally advanced stage when diagnosed, which has a poor five-year survival even after treatment.
For more information about head and neck cancer, call the UPMC Cancer Centers Cancer Information and Referral Service at 412-647-2811 or visit the Web site at http://www.upmccancercenters.com.