Blocking a cancer-friendly protein may lead to improved therapies for a difficult-to-treat form of lymphoma, according to City of Hope researchers. The findings were reported in the May 1 issue of Cancer Research.
|Anna Scuto studies how STAT3 interacts with cancer. (Photo by Darrin S. Joy)|
A team of scientists headed by Richard Jove, Ph.D., Morgan and Helen Chu Director’s Chair of Beckman Research Institute and professor of molecular medicine, and Anna Scuto, Ph.D., staff scientist in the Department of Molecular Medicine, found that blocking production of a protein called STAT3 stunted the growth of an aggressive form of lymphoma called activated B-cell-like diffuse large B-cell lymphoma.
This type of lymphoma responds poorly to existing therapies, Jove said, “but it continually expresses STAT3, so we thought suppressing the protein might be a very effective approach.”
Jove is a leading authority on STAT3 and its role in cancer development. His findings, along with those of other scientists, have shown that STAT3 both promotes the growth and spread of many cancers and helps protect tumor cells from the body’s immune system.
In the most recent study, the research team used short pieces of genetic material called shRNA that can target and turn off particular genes. They designed an shRNA aimed specifically at the STAT3 gene and used it to treat the lymphoma cells in the lab. They then injected one set of mice with the treated lymphoma cells and another set of mice with control cells, which are identical lymphoma cells that did not receive the anti-STAT3 shRNA.
After a few days, they checked to see if either set of mice showed signs of lymphoma and found that the mice that received treated lymphoma cells developed little or no cancer while the mice with control cells quickly developed tumors. This showed that blocking STAT3 can effectively suppress the lymphoma.
In addition, blocking STAT3 may provide a more focused treatment.
“The lymphoma cells depend much more on STAT3 for growth and survival than normal cells do, so blocking it affects the lymphoma cells more than normal cells,” Scuto said. “If we develop new therapies that target STAT3, we will be able to inhibit the lymphoma while limiting potential side effects.”
The researchers also found that blocking STAT3 drove the lymphoma cells to undergo apoptosis, a type of cellular suicide, while changing the local environment around the cancer to be less tumor-friendly.
“The results were very clear and show that including a STAT3 inhibitor in treatments targeting this form of lymphoma — and possibly other forms of cancer — could significantly improve outcomes,” Jove said.
The team next aims to develop methods for using STAT3-blocking shRNAs and to identify drugs that block STAT3 for testing in future clinical trials.
Other authors on the study include Maciej Kujawski, Ph.D., Claudia Kowolik, Ph.D., Ludmila Krymskaya, Ph.D., Lin Wang, Ph.D., Lawrence M. Weiss, M.D., David DiGiusto, Ph.D., Hua Yu, Ph.D., and Stephen J. Forman, M.D. The study was supported by the National Institutes of Health, the W.M. Keck Foundation and the Tim Nesvig Fellowship for Lymphoma Research Fund.