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Modified Vitamin D Shown to Make Pancreatic Cancer More Vulnerable to Chemotherapy

doi: 10.1097/01.COT.0000456292.72485.0f
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A synthetic derivative of vitamin D has been found by researchers at Salk Institute to collapse the barrier of cells shielding pancreatic tumors, making the “seemingly impenetrable” cancer much more susceptible to therapy.

By attacking the wound repair mechanism of fibrosis, the findings may also have implications for other difficult-to-treat tumors, such as lung, kidney and liver cancer, the senior author, Ronald Evans, PhD, a Howard Hughes Medical Institute investigator and Director of the Gene Expression Laboratory there, said in a news release.

“While the success of this drug in humans with pancreatic cancer is still unclear, the findings in animal studies were strong, raising hope that ongoing clinical trials will give people with this terrible disease hope for a truly new type of therapy.”

Figure. Eva

Figure. Eva

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SU2C Supported

The study, part of a Stand Up to Cancer-supported interdisciplinary initiative, is published in the Sept. 25 issue of Cell (2014;159:80-93).

Evans explained that it has been known that the ability of the pancreatic tumor to communicate with nearby cells—i.e., the tumor microenvironment—is key to its growth. “Tumor cells send out signals that make the microenvironment inflamed and dense, and this ‘living shield’ around a tumor not only helps the cancer grow, but blocks the access of immune cells and chemotherapeutic drugs, making the cancer particularly hard to treat.”

The hope was to discover how to restore this inflamed microenvironment to its normal, quiescent, state and weaken the wall around the tumor.

“There was evidence that the activation of the microenvironment was theoretically reversible, but nobody knew exactly what was responsible for the activation, making it hard to turn off,” said the study's first author, Mara H. Sherman, a postdoctoral research fellow.

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Pancreatic Stellate Cells

As explained in the news release, Sherman, Evans, and their collaborators focused on one component of this wall: pancreatic stellate cells, which usually respond to small injuries by briefly switching to an activated state, spurring new cell growth. In the case of cancer, however, the stellate cells near a tumor—in response to signals from the tumor—are constantly turned on.

This chronic activation provides the tumor cells with extra growth factors and helps them proliferate, but also forms a barrier around the tumor that protects it from chemotherapy.

Since previous research by Evans' group showed that stellate cells in the liver could be inactivated by a chemically modified form of vitamin D, the team wondered whether the same could hold true in the pancreas, despite the fact that the vitamin D receptor was not thought to be present in pancreatic tissue.

But when the differences between activated and inactivated stellate cells in the pancreas were investigated, it was found that activated stellate cells near a tumor had high levels of the vitamin D receptor. And when the researchers then added modified vitamin D to activated stellate cells, the cells quickly reverted back to a healthy, inactivated state, stopping production of signals that spur growth and inflammation.

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‘Big Surprise’

“This was a big surprise because vitamin D has been tried multiple times as a therapy for pancreatic cancer and never worked,” Evans said.

It turns out that activated stellate cells rapidly break down normal vitamin D, preventing the vitamin from binding to the receptor, he continued. But systematic analysis of vitamin D analogues allowed the team to discover a modified form of vitamin D that is more stable, resilient, and effective in vitro.

The researchers found that combining this new vitamin D-like compound drug with existing chemotherapeutics in mice resulted in a 50 percent increase in lifespan compared with use of chemotherapy alone.

“It's really remarkable, considering that vitamin D itself is not attacking the cancer cells,” said Michael Downes, PhD, a senior staff scientist at Salk and co-corresponding author of the study. “It's changing the environment to a more favorable setting needed for the chemotherapy drugs to work.”

Evans said that studies have shown that people deficient in vitamin D are more likely to develop pancreatic cancer, and based on the new results, healthy levels of vitamin D may help keep vitamin D receptor signaling in stellate cells normal and squash a cancer's growth—at least until a tumor itself forces the stellate cells to turn on.

“Recently, other research groups have explored the idea of destroying the microenvironment to weaken a tumor,” Downes said. “Our approach is very different. Instead of destroying, we simply want to reprogram the tumor microenvironment to a healthy state. This has the dual effects of delivering more drugs to the tumor as well as replenishing the tissue with normal stellate cells.”

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Clinical Trial

Evans' group has already teamed up with clinicians at the University of Pennsylvania to launch a clinical trial testing the effectiveness of using the vitamin D-like drug in cancer patients before pancreatic surgery. “Previous trials with vitamin D failed because they didn't understand the need for a special form of vitamin D and that for pancreatic cancer it must be used in combination with chemotoxic drugs,” Evans said.

“So, by re-thinking the problem, we have been able to open up a new route to the treatment of pancreatic cancer and, looking forward, hopefully other diseases as well.”

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iPad Extra!

VIDEO: In this Salk Institute-created video, which can be seen on the iPad edition of this issue, Ronald Evans, Mara Sherman, and Michael Downes explain their work that found that a specially created vitamin D-derivative makes tumors more vulnerable to chemotherapy, suggestimg that use of “vitamin D priming” could be a useful addition to therapy for pancreatic ductal adenocarcinoma.

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© 2014 by Lippincott Williams & Wilkins, Inc.
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