"This is a very exciting -- and surprising -- finding," says Daniel Billadeau, Ph.D., lead author of the report. To identify new target molecules with potentially therapeutic impact for a cancer for which there is currently no real useful treatment is incredibly important.
"Based on the literature, you would predict the opposite of what we found. But in fact, we determined that we can decrease a known regulator of cancer cell survival -- in effect, turn this regulator off -- and when we do, the pancreatic cancer cells undergo apoptosis (commit cell suicide) and die."
Significance of the Research
The Key Finding
The Mayo Clinic researchers discovered a previously unrecognized role in pancreatic cancer for the GSK-3 Beta molecule. They determined that GSK-3 Beta is vital to pancreatic cancer cell survival and growth through its effects on a well-known gene regulator called NF Kappa B (pronounced "en-ef-kappa-bee").
The NF Kappa B protein is well known to researchers as a transcription factor that regulates many genes. In cancer cells, NF Kappa B regulates genes involved in cancer cell survival, proliferation and blood vessel formation (angiogenesis). NF Kappa B is hyperactive in many human cancers including pancreatic. The Mayo Clinic study shows that in pancreatic cancer, the activity of NF Kappa B is regulated by GSK-3 Beta. Researchers determined this by showing that if they could decrease GSK-3 Beta protein or inactivate it using small molecular inhibitors, they could likewise decrease NF Kappa B -- and deprive the pancreatic cancer cells of a means to grow and survive.
Notably, in pancreatic cancer, NF Kappa B activity is high -- which can cause resistance to chemotherapy drugs used to treat the disease. This new information suggests a potential means of treating pancreatic cancer by a two-pronged attack of administering the gemcitabine in combination with a drug to block GSK-3 Beta.
Nearly all die within five years of diagnosis
Despite recent advances in understanding how cancers work at the molecular level, pancreatic cancer lacks an effective treatment. Approximately 30,000 Americans are diagnosed with pancreatic cancer annually, and the disease kills the same number each year. Ninety percent of these cancers are pancreatic ductular adenocarcinoma, the fourth leading cause of cancer deaths in the United States. Pancreatic cancer patients have one of the poorest prognoses -- the five-year survival rate is 3 percent. Because pancreatic cancer is aggressive, spreads rapidly and few treatment options are available, researchers welcome any promising leads for improving diagnosis and therapy.
Collaborators and Support
Other collaborators include Andrei Ougolkov; Martin Fernandez-Zapico, M.D.; Doris Savoy; and Raul Urrutia, M.D., all of Mayo Clinic. Their work was supported by National Cancer Institute and the Mayo Foundation.
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Cancer Research