A vitamin D-based therapy may help remodel the protective barrier around pancreatic tumors, offering a possible new way to make the disease more vulnerable to treatment.
A small clinical trial led by Dana Farber Cancer Institute found that paricalcitol, an FDA-approved vitamin D analog used for other conditions, could be safely combined with standard chemotherapy in patients with previously untreated metastatic pancreatic cancer.
Patients whose tumors had higher vitamin D receptor expression showed the best outcomes when treated with paricalcitol. Those patients responded more favorably to chemotherapy and had the longest overall survival in the study.
Paricalcitol With Chemotherapy
The study, published in Nature Cancer on May 25, included 36 patients with previously untreated metastatic pancreatic cancer. Patients received gemcitabine and nab paclitaxel with either a placebo, intravenous paricalcitol, or oral paricalcitol.
Paricalcitol is already approved for preventing and treating secondary hyperparathyroidism in people with chronic kidney disease, but it is not approved as a pancreatic cancer treatment.
The main goal of the trial was to assess safety. Overall, the combination was well tolerated, though five of the 12 patients who received oral paricalcitol developed elevated blood calcium levels, which were managed through standard dose reductions.
Tumor Barrier Penetrated
Pancreatic cancer is difficult to treat partly because tumors are surrounded by dense connective tissue that blocks drugs and suppresses immune activity.
Researchers found that paricalcitol reduced the activation of fibroblasts inside tumors without reducing the overall number of fibroblasts. Fibroblasts can form a protective barrier around pancreatic tumors and contribute to treatment resistance.
The treatment also increased T cell infiltration in tumors. T cells are immune cells that are often kept out of pancreatic tumors by the tumor microenvironment.
Still Early Stages
The trial was not designed to prove whether paricalcitol improves survival or treatment response. However, researchers observed stronger early signals among patients who received the vitamin D analog with chemotherapy.
Partial responses occurred in 10 of 24 patients who received paricalcitol, compared with one of 12 patients in the placebo group. Five patients in the paricalcitol groups remained progression-free after one year, while none in the placebo group reached that mark.
Research Built on Earlier Salk Work
The trial builds on earlier Salk Institute research showing that the vitamin D receptor can regulate fibroblast activity in the liver and pancreas.
Ronald Evans and colleagues previously found that synthetic vitamin D analogs such as paricalcitol could help block fibrosis and pancreatitis in preclinical studies. Their work also showed that vitamin D analogs could reverse the activation of cancer-associated fibroblasts and improve chemotherapy response in pancreatic cancer models.
“This study really takes a novel approach to cracking therapeutic resistance in pancreatic cancer,” study co-author Ronald Evans said.
Next Steps
The findings support larger clinical trials to test whether vitamin D analogs can improve survival when combined with chemotherapy or other cancer treatments.
Future studies are also expected to examine whether vitamin D receptor expression can help identify patients most likely to benefit from paricalcitol-based therapy.
The study also highlights a treatment approach based on repurposing an existing FDA-approved drug, which may offer less commercial incentive than developing a new drug but could provide a practical path for future cancer research.
