|Modified vitamin D can collapse the barrier of |
pancreatic cancer cells.
A synthetic derivative of vitamin D was found to collapse the barrier of cells shielding pancreatic tumors, making this seemingly impenetrable cancer much more susceptible to therapeutic drugs. The discovery has led to human trials for pancreatic cancer, even in advance of its publication today in the journal Cell. By attacking a wound repair mechanism called fibrosis, the findings may also have implications for other tough-to-treat tumors, such as lung, kidney and liver cancer.
Pancreatic cancer is one of the deadliest forms of cancer, a fact highlighted in recent years by the deaths of well-known figures such as Steve Jobs and Patrick Swayze. About 46,000 people are diagnosed in the United States each year and about 40,000 people die from the disease, according to the National Institutes of Health.
The researchers knew that the ability of the pancreatic tumor to communicate with nearby cells, called the tumor microenvironment, is key to its growth. Tumor cells send out signals that make the microenvironment inflamed and dense; 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 researchers wanted to figure out how to restore this inflamed microenvironment to its normal or “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. They focused their attention 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 of the stellate cells provides the tumor cells with extra growth factors and therefore helps them proliferate, but also forms a wall-like barrier around the tumor that protects it from chemotherapeutics and other cancer-fighting drugs.
In 2013, the group discovered that stellate cells in the liver could be inactivated by a chemically modified form of vitamin D. They wondered whether the same could hold true in the pancreas, despite the fact the vitamin D receptor was not thought to be present in pancreatic tissue. But indeed, when the group of researchers examined the differences between activated and inactivated stellate cells in the pancreas, they 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.
It turns out that activated stellate cells rapidly break down normal vitamin D, preventing the vitamin from binding to the receptor. 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.
To see whether this new vitamin D-like compound could halt the growth of a tumor, the team studied its effectiveness in mice. The researchers found that combining the drug with existing chemotherapeutics gave a 50 percent increase in lifespan compared to chemotherapy alone.
Studies have shown that people deficient in vitamin D are more likely to develop pancreatic cancer. Based on the new results, the researchers thinks that 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".
The group has already launched a clinical trial testing the effectiveness of using their vitamin D-like drug in cancer patients before pancreatic surgery.