Researchers Find New Target for Pancreatic Cancer Treatment

pancreatic cancer treatment
1902-06 056 1902-06 John Price Lab BYU Professor John C. Price in his lab. February 1, 2019 Photo by Jaren Wilkey/BYU © BYU PHOTO 2019 All Rights Reserved (801)422-7322

One of the biggest challenges to cancer therapy is that cancer cells adapt to their environment and become resistant to treatment. New research by BYU professor John Price and grad student Monique Speirs found a way to slow this adaptation process — technically called metabolic reprogramming — in one of the most difficult cancers to treat: pancreatic cancer.

In a paper recently published in biomedical journal Oncotarget, Price and Speirs detail how targeting specific growth-regulating cell lipids can interrupt metabolic reprogramming in pancreatic cancer cells. The duo were able to successfully target the lipids by inhibiting certain enzymes responsible for their production.

“When we inhibited one enzyme in particular (Sphingosine-Kinase 1), each cancer group, though distinct in terms of their environment, was more sensitive to chemotherapy,” Speirs said. “For cancers that show over expression of this enzyme, this could be a great drug target.”

To get to this point, Price and Speirs first observed pancreatic cancer cells placed in four different conditions and three environments, and looked for processes in the cancer cells that were not modifiable across all environments. “If we can target a nondisposable process we can be more effective at getting rid of them,” Price said.

To understand how each different environment affected the cells processes, Price and Speirs studied the cells’ metabolic pathways. These pathways are highly regulated by cellular signals, which can be compared to traffic lights on a road. In this analogy, “healthy cells are good, lawful drivers,” Speirs explained. “They tend to obey all the ‘regulations’ and produce the energy needed to grow at normal rates. Cancer cells would be unlawful drivers. They run all the red lights and ‘speed’ through or bypass the regulatory signals so they can divide rapidly.”

Cancer cells metabolize and divide so fast, they become subject to high levels of cellular stress. The cells react to this stress by rerouting their metabolism, like taking another route to avoid regulation. Then, the cells find new ways to produce what they need and suppress regulatory signals even further so they can continue to multiply. Different kinds of cellular lipids can act like traffic lights, giving the cells pro-growth or pro-death signals.

“Consistent with previous literature, we found that one lipid (Sphingosine-1-phosphate, S1P) acted as a pro-growth signal in metabolically reprogrammed cancer cells,” Speirs said. “We also found another lipid (C16 Ceramide, C16 Cer) increased sensitivity to cell death inducing drugs. So, S1P is like a green traffic light signaling these cells to resist cell death and proliferate, whereas C16 Cer is like the red traffic light to signal cell growth arrest and cell death. “

This suggests that even though every patient’s body creates a different environment for their cancer, targeting the enzymes that produce these lipids may be a better treatment for cancer. Sphingosine-Kinase 1 (SK1) is an enzyme that catalyzes the transformation of S1P from C16 Cer. Price and Speirs found that this enzyme was either overexpressed or hyperactivated in all four cancer cell groups.

Knowing what signals the cancer is using to increase cell growth rates could potentially give health care professionals the ability to control the activity of enzymes underlying cancerous cell behavior, and shift the lipid signals back to a healthy balance.

“That by itself might not be ‘the cure’ but it would stop the growth,” Price said. “That would be preferable to a traditional nuclear blast chemotherapy approach.”

Pancreatic cancer is well known for becoming chemo resistant, which made it a good target for this research. Price and Speirs expect that other cancer cells are doing something very similar, though they haven’t tested it yet.