PITTBURGH, July 11 - Researchers from the University of Pittsburgh School of Medicine report a significant new advance in the search for an effective treatment for human liver cancer in the July issue of Molecular Cancer Therapeutics. Using a newly available monoclonal antibody, they demonstrated significant reductions in tumor cell proliferation and survival in human and mouse hepatocellular cancer (HCC) cell lines. According to the researchers, this finding has significant implications not only for the treatment of liver cancer but for a number of different types of cancer.
Most cases of HCC are secondary to either a viral hepatitis infection or cirrhosis of the liver. Despite recent advances, it remains a disease of grim prognosis due to the poorly understood mechanism of how the disease originates and spreads. Most patients live only a short time after diagnosis.
Based on previous studies showing that some pathways that were previously thought to be active only during fetal liver development, particularly the class III receptor tyrosine kinase (RTK) family pathway, became highly active again in the liver of HCC patients, Satdarshan P. Singh Monga, M.D., associate professor, division of cellular and molecular pathology and colleagues at the University of Pittsburgh School of Medicine, obtained rat and human liver cancer cell lines and analyzed them for level of expression of an RTK protein known as platelet-derived growth factor receptor-alpha, or PDGFRá. The investigators also analyzed the cells for their level of activation of the PDGFRá gene.
At an early fetal stage of liver development in the mouse, the investigators found that the level of expression of PDGFRá was 37 times higher compared to later stages of development in the adult mouse liver. They also found significantly higher levels of PDGFRá in rat and human liver cancer cell lines as compared to normal cells in culture.
Dr. Monga's group then treated human and mouse liver cancer cell lines with a monoclonal antibody targeted against PDGFRá. It resulted in a significant decrease in tumor cell proliferation and a marked increase in tumor cell death. In fact, all tumor cell lines experienced significant decreases in proliferation in response to the monoclonal antibody and there was a 4- to 18-fold increase in programmed cell death, or apoptosis, among the cancer cell lines compared to normal control cells.
According to Dr. Monga, these results suggest that PDGFRá offers an important new therapeutic target for the treatment of HCC.
"We are very excited because this is the first targeted therapy for liver cancer. Other therapies have some modest benefits, but no one knows exactly how they work. We now have identified a pathway that appears to be overly active in more than 70 percent of the cancers we examined and, when targeted, leads to significant reduction in tumor cell proliferation and survival," said Dr. Monga.
More importantly, targeting the PDGFRá pathway in liver cancer cells does not appear to affect normal liver cells, making the treatment relatively non-toxic. "Normally, regenerating liver cells are not exclusively dependent on this pathway, and it is not overly active in other types of cells. So this monoclonal antibody is a highly targeted treatment for this disease," he added.
Furthermore, because high expression of PDGFRá has been detected in a variety of tumors, such as skin cancer, brain tumors, gastrointestinal tumors, prostate tumors, ovarian cancer and leukemia, Dr. Monga believes these findings could have much broader applications.
This research was funded by grants from the American Cancer Society and the National Institutes of Health as well as the Cleveland Foundation and the Rango's Fund for Enhancement of Pathology Research.
In addition to Dr. Monga, other researchers involved in the study included Peggy Stock, Xinping Tan and Amanda Micsenyi, all in the department of pathology, University of Pittsburgh School of Medicine; Dulabh Monga, department of human oncology, Allegheny General Hospital, Pittsburgh; and Nick Loizos, ImClone Systems, Inc., New York.