Researchers have identified one reason pancreatic cancer is so resistant to chemotherapy treatment: vitamin D.
Only about 5 percent of pancreatic-cancer patients survive beyond five years even with the most aggressive treatment, according to the National Cancer Institute. One big reason is that chemotherapy — including the standard drug, gemcitabine — isn’t very effective at preventing pancreatic cancer cells from replicating.
To understand why, Timothy J. Yen, a professor at Temple University’s Fox Chase Cancer Center in Philadelphia, removed each of the 24,000 genes, one by one, in pancreatic cancer cells and then doused them with gemcitabine.
When some of these genes were “knocked out,” the gemcitabine was effective. One in particular surprised the researchers.
“When we knocked out the gene for a protein that binds to vitamin D, almost all of (the cancer cells) died,” said Yen, the leader of the research team.
Although vitamin D is important for health, especially for bone health, normal cells do not need vitamin D to survive, said Yen. Apparently, though, pancreatic cancer cells do.
That means if scientists can figure out a way to inactivate the vitamin D receptor in pancreatic cancer cells, the main drug used to treat patients would be more effective.
“My excitement about making vitamin D receptors a priority is because it is a ‘druggable’ target,” Yen said. “There are compounds out there that drug companies already make to affect vitamin D,” so the apparatus and knowledge already exist.
The researchers at Fox Chase Cancer Center, which is part of the Temple University Health System, published their findings in the journal Cell Cycle on Jan. 3. Their study took nearly four years to complete, and the initial findings were so unexpected, Yen said, that many more-sophisticated experiments were performed to convince the team that their findings were correct.
“I didn’t believe the results at first,” he said, “because the literature on vitamin D — what does it have to do with cancer? But this wasn’t just a fluke.”
Yen admits that he and his team are novices when it comes to vitamin D, but they did know that it aids functioning in nearly every tissue and organ of the human body, not just the bones. What was so unusual in their genetic experiments was to find that while normal cells do not require vitamin D to survive, pancreatic cancer cells need it to repair the damage caused by chemotherapy.
“This in-vitro study was quite elegant and suggested that targeting VDR (vitamin D receptors) may show synergistic effect with gemcitabine in pancreatic cancer patients,” said Haoqiang Ying, an expert in molecular and cellular oncology at the University of Texas MD Anderson Cancer Center in Houston. “Much more detailed studies are needed.”
Many researchers have examined how tumor cells hijack genes, according to Yen.
“Why they hijack certain genes we don’t know,” he said. “But they do re-purpose other genes to help the cancer to survive. In the case of pancreatic cancer, it’s the (gene for the) vitamin D receptor.”
Another reason pancreatic cancer is so stubborn to treat is that the malignancy creates a kind of moat around itself, making it difficult for chemo drugs to reach the primary tumor.
“The possibility is, if we can design something to inhibit vitamin D, we can enhance the sensitivity of the tumor to the limited amount of the drug that gets through,” Yen said. “I would love to see the day my research gets to the bedside, but there are so many things to overcome. This is just another light switch we’ve turned on. We just hope to keep it on as long as we can.”