A small clinical trial led by Dana-Farber Cancer Institute researchers tested the Salk Institute’s idea: that activating the vitamin D receptor can help reshape the protective environment around pancreatic tumors in ways that could make the notoriously difficult-to-treat cancer more vulnerable to therapeutic treatments.
In the study, published May 25, 2026, in Nature Cancerpatients with previously untreated metastatic pancreatic cancer received standard chemotherapy with or without paricalcitol, a vitamin D analog already approved by the FDA for other uses. In patients receiving oral or intravenous paricalcitol, the combination was found to be safe and reduce fibroblast activation in the tumor microenvironment, validating Salk’s preclinical findings.
The trial was not designed to measure how well the approach works in treating pancreatic cancer, but the researchers observed improved chemotherapy responses and increased progression-free survival at one year among patients who received paricalcitol plus chemotherapy. In addition, they found that patients with high vitamin D receptor expression and who received paricalcitol had the longest overall survival.
This study really takes a new approach to eliminating treatment resistance in pancreatic cancer. By using vitamin D analogs to engage the body’s own natural system for mitigating fibrotic and inflammatory responses, we can allow other therapies to do their work.”
Ronald Evans, PhD, study co-author, professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk
How did the basic research lead to this clinical trial?
Evans discovered the nuclear receptor superfamily, an important group of molecules that includes the vitamin D receptor. When activated by certain hormones, vitamins or lipids, nuclear receptors turn genes on and off to govern cell behavior. Today, approximately 13% of all FDA-approved drugs work by targeting nuclear receptors.
Evans and team also revealed that the vitamin D receptor regulates fibroblasts in the liver and pancreas in preclinical models. Fibroblasts, cells that make up connective tissue, form the protective shield that often surrounds the pancreas and other tumors.
These landmark studies showed that the vitamin D receptor is highly expressed in rare populations of tissue-resident fibroblasts and is critical for maintaining tissue health and stability. Evans’ team also showed that they could block liver fibrosis and pancreatitis with synthetic vitamin D analogs, such as paricalcitol, which are designed to counteract the natural mechanism that degrades vitamin D.
Since a strong, fibrotic response is a hallmark of pancreatic tumors, Evans’ team next looked at how these treatments affect the pancreatic cancer microenvironment—the tumor environment. They were surprised to find that, in pancreatic cancer models, vitamin D analogs could reverse the activation of cancer-associated fibroblasts and, in turn, promote chemotherapy responses.
These previous findings provided one of the first examples of a new therapeutic approach for pancreatic cancer: reprogramming the supportive microenvironment that surrounds and protects pancreatic cancer cells.
From bench to bedside: What did the clinical trial do and what did it find?
Building on these seminal findings from Salk and in collaboration with the Evans group, Brian Wolpin, MD, MPH, and Kimberly Perez, MD, at the Dana-Farber Cancer Institute, led a randomized, safety-focused clinical trial of the effect of vitamin D analogs in pancreatic cancer.
For this trial, 36 participants with previously untreated metastatic pancreatic cancer were assigned to standard chemotherapy (gemcitabine plus nab-paclitaxel) plus either placebo, intravenous paricalcitol, or oral paricalcitol. Paricalcitol is an FDA-approved drug used to prevent and treat secondary hyperparathyroidism in patients with chronic kidney disease.
The primary objective of the trial was to assess the safety of adding paricalcitol to chemotherapy. Paricalcitol was administered safely overall with chemotherapy, although five of 12 participants receiving oral paricalcitol experienced elevated blood calcium, which was manageable through standard dose reductions.
A critical secondary objective of this trial was to determine whether molecular or cellular changes occurred in patients treated with paricalcitol. To accomplish this, researchers collected paired biopsies from patients at screening and again after four to six weeks of treatment. The team analyzed the samples with state-of-the-art immunofluorescence multiplexing and spatial transcription methods to study changes in tumor cell populations and microenvironment. They found that paricalcitol reduced the activation of fibroblasts within the tumors (but not their total number) and increased the infiltration of T cells, a type of immune cell that is typically excluded from tumors. These findings validated the potential of paricalcitol as a tumor microenvironment remodeling therapy.
Although the study was not designed to compare treatment effectiveness or patient outcomes, the researchers did see a difference. Partial responses to treatment were more common among patients receiving paricalcitol (10 in 24 or 42%) than among those receiving placebo (one in 12 or 9%). In addition, more paricalcitol-treated patients were progression-free at one year (five patients) than in the placebo group (none).
The researchers also found that the patients differed in the levels of the vitamin D receptor in their tumors. In addition, they found that vitamin D receptor levels were associated with outcomes—patients with high vitamin D receptor levels who received paricalcitol had a better response to chemotherapy and the longest overall survival time after treatment.
Why is this important?
Pancreatic cancer remains one of the most difficult cancers to treat. Standard chemotherapy can slow the disease for some patients, but outcomes remain poor and the tumor microenvironment is widely believed to contribute to treatment resistance. Pancreatic tumors are often surrounded by dense, fibroblast-rich connective tissue, creating a barrier that prevents delivery of therapeutic drugs and creates an immunosuppressive microenvironment.
What’s next?
Findings from this trial set the stage for larger clinical studies designed to evaluate how combining vitamin D analogs with chemotherapy or other cancer treatments affects survival outcomes. Furthermore, future work is needed to test whether baseline expression of vitamin D receptors can serve as a reliable biomarker of patient responses to combination therapies, including vitamin D analogues.
“This study is an important step forward in the use of a vitamin D analog as a stromal remodeling therapy that can overcome therapeutic resistance in the pancreas,” says Perez. “Building on fundamental basic research at the Salk Institute, it validates these preclinical findings in patients and provides a roadmap for future studies that could one day create a new standard of care.”
