Vitamin D Drug Shows Surprising Promise Against One of the Deadliest Cancers

A vitamin D-based therapy may help remodel the protective barrier surrounding pancreatic tumors, offering a potential new treatment strategy.

Pancreatic cancer is notoriously difficult to treat in part because tumors surround themselves with a dense, protective barrier that blocks drugs and suppresses immune activity. Now, a small clinical trial led by researchers at Dana-Farber Cancer Institute suggests that an FDA-approved vitamin D analog may help dismantle some of those defenses, potentially making tumors more vulnerable to treatment.

The study, published in Nature Cancer, enrolled patients with previously untreated metastatic pancreatic cancer who received standard chemotherapy either with or without paricalcitol, a vitamin D analog already approved by the FDA for other conditions. Researchers found that adding paricalcitol, given either orally or intravenously, was safe and reduced fibroblast activity within the tumor microenvironment, confirming earlier findings from Salk laboratory studies.

Although the trial was not designed to evaluate treatment effectiveness, patients who received paricalcitol alongside chemotherapy showed higher response rates and improved progression-free survival after one year. Researchers also found that patients whose tumors had high levels of vitamin D receptor expression experienced the longest overall survival when treated with paricalcitol.

“This study really takes a novel approach for cracking therapeutic resistance in pancreatic cancer,” says study co-author Ronald Evans, PhD, professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. “By using vitamin D analogs to engage the body’s own natural system for dampening fibrotic and inflammatory responses, we can enable other therapies to do their job.”

How the Vitamin D Receptor Reprograms Fibroblasts

Evans discovered the nuclear receptor superfamily, a major group of molecules that includes the vitamin D receptor. These receptors respond to specific hormones, vitamins, and lipids by turning genes on or off, helping regulate cell behavior. Today, roughly 13% of FDA-approved drugs target nuclear receptors.

Evans and his colleagues previously found that the vitamin D receptor regulates fibroblasts in the liver and pancreas in preclinical studies. Fibroblasts are connective tissue cells that can form a protective barrier around pancreatic tumors and other cancers.

Their research showed that the vitamin D receptor is highly active in rare populations of tissue-resident fibroblasts and plays an important role in maintaining tissue stability and health. The team also demonstrated that synthetic vitamin D analogs such as paricalcitol, which are designed to resist the body’s natural vitamin D breakdown process, can block liver fibrosis and pancreatitis.

Because pancreatic tumors are characterized by a strong fibrotic response, the researchers investigated how these compounds affect the tumor microenvironment. In pancreatic cancer models, they found that vitamin D analogs could reverse the activation of cancer-associated fibroblasts and improve responses to chemotherapy.

These discoveries helped establish a new treatment strategy for pancreatic cancer focused on reprogramming the supportive environment that surrounds and protects tumor cells.

Clinical Trial Tests Paricalcitol Plus Chemotherapy

Building on this work and collaborating with the Evans laboratory, Brian Wolpin, MD, MPH, and Kimberly Perez, MD, of Dana-Farber Cancer Institute conducted a randomized clinical trial focused on the safety of vitamin D analogs in pancreatic cancer.

The study included 36 patients with previously untreated metastatic pancreatic cancer. Participants received standard chemotherapy (gemcitabine plus nab-paclitaxel) along with either a placebo, intravenous paricalcitol, or oral paricalcitol. Paricalcitol is approved to prevent and treat secondary hyperparathyroidism in people with chronic kidney disease.

The primary objective was to determine whether paricalcitol could be safely combined with chemotherapy. Overall, the treatment combination was well tolerated. Five of the 12 patients receiving oral paricalcitol developed elevated blood calcium levels, but these cases were managed through standard dose reductions.

Researchers also wanted to determine whether paricalcitol produced measurable molecular or cellular changes. To investigate this, they collected tumor biopsies before treatment and again after four to six weeks. The samples were analyzed using advanced multiplex immunofluorescence and spatial transcriptomic techniques to examine changes in tumors and surrounding cell populations.

Tumor Microenvironment Changes and Immune Cell Infiltration

The results showed that paricalcitol reduced fibroblast activation within tumors without decreasing the overall number of fibroblasts. It also increased the presence of T cells, immune cells that are often largely excluded from pancreatic tumors. These findings support paricalcitol’s potential as a therapy that reshapes the tumor microenvironment.

While the trial was not intended to compare treatment outcomes, researchers observed notable differences between groups. Partial responses occurred in 10 of 24 patients (42%) who received paricalcitol, compared with one of 12 patients (9%) who received a placebo. Five patients in the paricalcitol groups remained progression-free after one year, while none in the placebo group achieved that outcome.

The team also found significant variation in vitamin D receptor levels among patients’ tumors. Higher receptor expression was associated with better outcomes. Patients with elevated vitamin D receptor levels who received paricalcitol responded more favorably to chemotherapy and experienced the longest overall survival.

Biomarker Potential and Future Treatment Directions

Pancreatic cancer remains one of the most challenging cancers to treat. Although chemotherapy can slow disease progression for some patients, outcomes are generally poor. Researchers believe the tumor microenvironment plays a major role in treatment resistance. Dense connective tissue rich in fibroblasts can limit drug delivery and create an immune-suppressing environment around tumors.

The findings support larger clinical trials to determine whether combining vitamin D analogs with chemotherapy or other cancer treatments can improve survival. Future research will also explore whether vitamin D receptor expression before treatment can serve as a reliable biomarker for identifying patients most likely to benefit from these therapies.

“This study is an important step forward for the use of a vitamin D analog as a stromal remodeling therapy that can overcome therapeutic resistance in pancreatic,” says Perez. “It was built upon foundational basic research at the Salk Institute, validates those preclinical findings in patients, and provides a road map for future studies that could someday establish a new treatment standard.”

Reference: “Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: a randomized, multiarm, run-in phase trial” by Kimberly J. Perez, Andressa Dias Costa, Alexander Jordan, Thomas B. Karasic, Dalia Elganainy, Suryun Kim, Chen Yuan, Dan Y. Gui, Runzi Tan, Sung Chul Hong, Xi Wang, Simona Cristea, Emma Coleman, Morgan Truitt, Tae Gyu Oh, Hui Zheng, C. Sloane Furniss, Lauren Brais, Alexandra Bird, Josh Remland, Vasilena Gocheva, Jennifer S. Thalappillil, Mark Anderson, James M. Cleary, Andrea Enzinger, Marios Giannakis, Kimmie Ng, Douglas A. Rubinson, Benjamin Schlechter, Rishi Surana, Harshabad Singh, Thomas Abrams, Ursina Teitelbaum, Natallia Izgur, Eliezer Allen, Peter S. Winter, Srivatsan Raghavan, Jen Jen Yeh, Daniel Von Hoff, Christopher Liddle, Michael Downes, Ronald M. Evans, Peter O’Dwyer, Andrew Aguirre, Jonathan A. Nowak and Brian M. Wolpin, 25 May 2026, Nature Cancer.
DOI: 10.1038/s43018-026-01165-8

While many clinical trials rely on industry funding, this study tested an approach that repurposes FDA-approved medications already in routine clinical use, with limited opportunity for commercial returns.

This work was made possible by federal granting agencies and private philanthropists: the U.S. National Institutes of Health (grants K08 CA260442, P30 014195, P01 CA265762, U01 CA210171, P50 CA127003), Stand Up to Cancer-Cancer Research United Kingdom-Lustgarten Foundation Superenhancer Dream Team Award, Stand Up to Cancer-American Association for Cancer Research-Lustgarten Foundation VDR Agonist Team Award, Dana-Farber Cancer Institute, Hale Family Center for Pancreatic Cancer Research, Claudia Adams Barr Program in Innovative Basic Cancer Research, Lustgarten Foundation for Pancreatic Cancer Research (122215393), Don and Lorraine Freeberg Foundation, David C. Copley Foundation, Wasily Family Foundation, Paul M. Angell Family Foundation, Pancreatic Cancer Action Network, Noble Effort Fund, Wexler Family Fund, Promises for Purple, and Bob Parsons Fund.

ClinicalTrials.gov identifier: NCT03520790.

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