Researchers at Mayo Clinic in Florida have identified a new target to improve treatment of pancreatic ductal adenocarcinoma cancer, which accounts for more than 95 percent of pancreatic cancer cases. This fast-growing, often lethal cancer is resistant to conventional chemotherapy.
The findings are published in the Jan. 3 online issue of PLOS ONE.
The researchers decoded a molecular pathway that is switched "on" at all times, promoting accelerated growth of pancreatic tumors, and that discovery revealed ways to disable the pathway. They say one strategy could involve the use of the drug bortezomib, which is already approved for several human blood cancers.
"Targeting this pathway to decrease the proliferation of cancer cells may represent a new strategy for pancreatic cancer therapy," says the study's senior investigator, Peter Storz, Ph.D., a biochemist and molecular biologist at Mayo Clinic.
One feature of pancreatic cancer is increased activity of the transcription factor NF-kB, which turns on expression of genes that keep the cells proliferating and protect them from death. There are two pathways, known as the classical and alternative, by which NF-kB can be activated, and the researchers looked at the alternative pathway -- one in which NF-kB is activated differently, and which switches on other genes, compared to the classical signaling pathway. Both the classical and alternative pathways are active in pancreatic cancer.
The research team discovered that increased activity of the alternative NF-kB pathway results from suppression of TNF receptor-associated factor 2, or TRAF2. Loss of TRAF2 promotes fast growth of pancreatic tumors and correlates with increased aggressiveness, Dr. Storz says.
They tested this discovery in 55 human samples of pancreatic cancer, and found that in 69 percent, TRAF2 wasn't functioning properly and there were higher levels of other molecules participating in the alternative pathway.
A cocktail of drugs that includes chemotherapy, bortezomib and other inhibitors of molecules activated along the pathway may help pancreatic cancer patients, Dr. Storz says.
"Of course, this hypothesis requires extensive clinical testing, but our findings offer a new direction to investigate in improving treatment of pancreatic cancer," he says.
The research team includes cancer biologists Heike Dφppler and Geou-Yarh Liou, Ph.D. from Mayo Clinic in Florida. The study was funded by grants from the American Association for Cancer Research and the National Institutes of Health (grant numbers CA135102, CA140182 and P50CA102701).
- Dφppler H, Liou G-Y, Storz P. Downregulation of TRAF2 Mediates NIK-Induced Pancreatic Cancer Cell Proliferation and Tumorigenicity. PLoS ONE, 2013; 8(1): e53676 DOI: 10.1371/journal.pone.0053676
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