One of the reasons pancreatic cancer is so difficult to treat doesn’t have to do with the tumor cells themselves but with the dense mesh of extracellular matrix surrounding them. In pancreatic cancer, fibroblasts become activated, leading to the production of this physical barrier that is thought to reduce the effectiveness of chemotherapy. This matrix also promotes an immunosuppressive environment around the tumors, preventing immune cells from attacking the cancer, allowing it to flourish.
However, an ingredient in sunshine may be the key to breaking through this dense fibrosis: vitamin D. Scientists have previously reported that activating the vitamin D receptor (VDR) in pancreatic fibroblasts while also administering chemotherapy could prevent fibrosis and extend survival in mouse models of pancreatic cancer.1
Now, after more than a decade since this preclinical work, researchers have conducted the first clinical trial of a VDR agonist, called paricalcitol, in combination with chemotherapy in patients with metastatic pancreatic cancer.2 They found that the combination therapy was generally safe, and while the trial was not powered to test efficacy, the team noticed positive trends in patients who expressed VDR at higher levels compared to those who did not, suggesting a potential sub-group of patients for whom the treatment may work better.
“The data from this trial are very promising,” said Kenneth Olive, who studies pancreatic cancer at Columbia University Irving Medical Center and was not associated with the study. He explained that prior attempts to attack pancreatic cancer-associated fibroblasts have not extended survival times in clinical trials, but because paricalcitol acts differently from those other methods, it may prove more effective. “This is a pretty exciting moment for the entire field of pancreatic cancer researchers who study the tumor microenvironment as a means of going after the tumor,” he added.
From Nuclear Receptors to Pancreatic Fibroblasts
VDR is just one member of the superfamily of nuclear receptors that Ronald Evans, a molecular biologist at the Salk Institute and coauthor of the new study, has discovered in his prolific career. But in the beginning, its potential connection to pancreatic cancer wasn’t even on his radar.
“It was totally by accident,” he said, about how he got into pancreatic cancer research. “I actually was asked to start a meeting in pancreatic cancer, and I didn't want to do it because we weren't [studying] that,” Evans said. He explained how one presenter began talking about stellate cells in the pancreas, which can become activated fibroblasts, and he remembered thinking, “Those are supposed to be in the liver not in the pancreas,” he said. He spoke to the speaker after her talk, and the discussion opened a brand-new research avenue for him and his team.
“I got really excited about it,” Evans said. “Some early studies that we did really made it clear [that] this is a program that is functional and can actually have an impact.”
Morgan Truitt, a postdoctoral researcher in Evans’ lab and a coauthor of the study, explained that in a healthy pancreas, most cells do not express VDR, but, “it turns out it's there, and it's very highly expressed in these resident fibroblast populations,” he said. These pancreatic stellate cells may be rare, but they are important for maintaining tissue homeostasis.
Prior work from Evans’ group in pancreatic cancer mouse models showed that VDR agonists can change fibroblast gene expression such that it shifts the cells out of an activated state, and when researchers administered a VDR agonist in parallel with chemotherapy, the mice survived longer.1 Translating these results from mice into humans in a clinical trial took longer than Evans and his team hoped.
“Paricalcitol is FDA approved. It's also off patent, so it's hard to get an industry-sponsored trial for something that's off patent,” said Truitt. However, philanthropic organizations including Stand Up to Cancer and the Lustgarten Foundation supported the trial. So, with their clinical partners, including medical oncologists Brian Wolpin and Kimberly Perez at the Dana-Farber Cancer Institute, they started the first clinical trial testing a VDR agonist and chemotherapy in people.
VDR Agonist Plus Chemotherapy Proves Safe in Humans
The researchers enrolled 36 people with metastatic pancreatic cancer in the small clinical trial. They split the participants into three groups: chemotherapy plus oral paricalcitol, chemotherapy plus intravenous paricalcitol, and chemotherapy plus an oral placebo. The team found that while all formulations of the drug combination were generally safe, five patients in the chemotherapy plus oral paricalcitol group had some adverse reactions that required them to receive a lower dose of paricalcitol.
“Anytime you can give a patient an oral drug, it just makes treatment so much easier,” said Truitt. “It does need to be managed as an oral treatment, but it's very manageable.”
The team also took tumor biopsies from the participants both before and after treatment and used multiplex immunofluorescence and spatial transcriptomics to analyze the pharmacodynamics of the combination therapy. The researchers found that the clinical results mirrored what they had seen in the mouse models: After treatment, the proportion of activated fibroblasts decreased and there was an influx of T cells into the tumor microenvironment, indicating less fibrotic activity and less immunosuppression. They also noticed that VDR protein expression varied across the patient population and that—from their limited data set—VDR expression level correlated with tumor response to the combination therapy.
“High levels of VDR might actually really indicate responders, and that needs to be formally tested in follow-up studies,” said Truitt.
University of Pennsylvania pancreatic cancer researcher and physician, Ben Stanger, who was not involved in the study, was impressed by how well the team executed a difficult clinical trial. “Being able to evaluate biopsies pre-treatment and on-treatment, there's just a lot of complexity involved in that. But it's important that these kinds of studies are done because in many cancers, especially pancreas cancer, the microenvironment is critically important for the progression of the disease,” he said.
One limitation of the study, Stanger noted, was inherent heterogeneity in the biopsy samples. For example, taking a sample of a tumor, waiting a few months, and then taking another sample from a different part of the tumor or a different tumor altogether will introduce its own variability, he explained. “If you have a very big study, the numbers can overcome that heterogeneity, but in a small study like this, it does raise that question,” he said.
Olive agreed that the next step should be a trial with more participants to test how efficacious the combination therapy is. However, with the recent announcement of daraxonrasib’s doubling of survival time in metastatic pancreatic cancer—causing an unprecedented mid-presentation standing ovation from oncologists at this year’s American Society of Clinical Oncology meeting—the standard of care is likely to change to this new RAS inhibitor.
He added that just because daraxonrasib may become the new standard for pancreatic cancer treatment, that doesn’t mean this VDR research is not needed. “Everyone [with metastatic pancreatic cancer] progresses still for the most part,” he said. “Right now, we want to have multiple types of options to treat patients with, so I still think there's value for this combination [with chemotherapy]. But I also think it would be really wonderful to look at the VDR agonist in combination with RAS inhibitors.”
Stanger added that RAS inhibitors also induce changes in the pancreatic tumor microenvironment. “I could certainly see the potential to try this vitamin D approach in combination with a RAS inhibitor, but the cautionary note is we really need to know whether the effects on the microenvironment are good or bad.”
Evans and Truitt are eager to move paricalcitol plus chemotherapy or another drug like daraxonrasib forward too. They are working on preclinical experiments with different combinations that will inform future clinical work. “The science supports that these fibroblastic responses that you see in pancreatic cancer really create this general therapeutic resistance, so there's nothing per se specific about chemotherapy for this,” Truitt said. Evans added, “There's been new studies with new therapies, and we think that the combination of the format that we have along with the newer therapeutics might synergize.”
- Sherman M, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159(1):80-93.
- Perez KJ, et al. Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: A randomized, multiarm, run-in phase trial. Nat Cancer. 2026.
