McGowan Institute faculty member, Satdarshan P. Singh Monga, MD, associate professor, division of cellular and molecular pathology, and colleagues at the University of Pittsburgh School of Medicine report on a finding that has significant implications not only for the treatment of liver cancer but for a number of different types of cancer as well. Using a newly available monoclonal antibody, they demonstrated significant reductions in tumor cell production and survival in human and mouse liver cancer cell lines.
Based on previous studies and thought to be active only during fetal liver development, the class III receptor tyrosine kinase (RTK) family pathway became highly active again in the liver of liver cancer patients. Dr. Monga and his team 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 PDGFRa. The investigators also analyzed the cells for their level of activation of the PDGFRa gene.
At an early fetal stage of liver development in the mouse, the investigators found that the level of expression of PDGFRa was 37 times higher compared to later stages of development in the adult mouse liver. They also found significantly higher levels of PDGFRa in rat and human liver cancer cell lines as compared to normal cells in culture.
Upon treating the human and mouse liver cancer cell lines with a monoclonal antibody targeted against PDGFRa, the team found there were 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. There was also a 4- to 18-fold increase in programmed cell death, or apoptosis, among the cancer cell lines compared to normal control cells. These results suggest that PDGFRa offers an important new therapeutic target for the treatment of liver cancer.
“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.
Because high expression of PDGFRa has been detected in a variety of tumors—skin cancer, brain tumors, gastrointestinal tumors, prostate tumors, ovarian cancer, and leukemia—Dr. Monga believes these findings could have much broader applications.
Illustration: McGowan Institute for Regenerative Medicine.
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