Pancreatic cancer is nasty, sneaky and nearly impervious to the effects of chemotherapy, and its dispiriting five-year survival rate of 6 percent has budged not at all in decades. But researchers at the Salk Institute in California reported this week that they have found a way to unmask this stone-cold killer and render it vulnerable to standard cancer treatments.
Using a chemically modified version of vitamin D, the Salk scientists appear to have kicked open the doors to the vault within which pancreatic tumors flourish — in mice, at least. That exposes this most inexorable of cancers to the tender mercies not only of the immune system, but of chemotherapy as well.
In mice with pancreatic ductal adenocarcinoma, the addition of this vitamin D analog, called Calcipotriol, to chemotherapy prolonged survival by 57 percent over chemotherapy alone. Treated with a regimen of the cancer drug gemcitabine-plus-Calcipotriol, almost 3 in 10 of the mice in their experiments were considered “long-term” survivors: They lived an average of 53 days after treatment began, three to four times longer than those who got gemcitabine alone.
In the realm of pancreatic cancer research, that’s a first, said Salk Institute researcher Ronald Evans, senior author of the study, published in Cell this week. In research involving other types of cancers, the appearance of long-term survivors is “a sign you’re on the right track,” said Evans.
Even before the publication of the Salk team’s discovery, the Food and Drug Administration gave the go-ahead to human trials on the Calcipotriol-plus-chemotherapy approach to treating pancreatic cancer. Early human trials to flesh out the safety and dosages of the adjuvant to cancer therapy are underway at University of Pennsylvania and at the Translational Genomics Research Institute in Phoenix.
The Salk team’s approach to attacking hard-to-reach cancers is novel. Instead of attacking cancer cells themselves, or trying to destroy the complex of supportive structure that grows up around a tumor, Evans said, his lab has looked for ways to genetically reprogram the microenvironment within which tumor cells grow unchecked.
In pancreatic cancer, that has meant finding a way to get the tumor to shed the “invisibility cloak” that grows up around it and makes it invisible to the immune system and immune to the effects of chemotherapy medicines.
The pancreas’ evolved response to injury or infection, the activation of these pancreatic stellate cells is useful in walling off bacteria or dying tissue and limiting its damage. But when these cells build a wall around a tumor, they provide it everything it needs to grow as well as protect it from immune cells or chemotherapy medicine.
Researchers have long believed that vitamin D might be the key to inactivating the pancreas’ stellate cells, but previous efforts have failed because even a diseased pancreas was highly effective at breaking down this fat-soluble vitamin. Evans’ team was convinced that vitamin D indeed held the key to reprogramming the environment that sustained pancreatic tumors; they just had to find an analog of the vitamin that could not be dismantled by the pancreas.
Calcipotriol was that variant.
Evans said his team is hopeful that the unique approach to cancer-fighting that is at the heart of the latest research — to genetically reprogram the microenvironment within which tumor cells grow unchecked — will be useful in a wide range of cancers.