A small clinical trial led by researchers at Dana Farber Cancer Institute has tested a treatment strategy that began with laboratory discoveries at the Salk Institute. The idea is to activate the vitamin D receptor and, in doing so, alter the protective environment surrounding pancreatic tumors. That change could potentially make this notoriously difficult cancer more vulnerable to existing treatments.
The study, published in Nature Cancer, included patients with previously untreated metastatic pancreatic cancer. Participants received standard chemotherapy either alone or in combination with paricalcitol, a vitamin D analog already approved by the FDA for other medical uses. Whether paricalcitol was given by mouth or intravenously, researchers found that it could be combined safely with chemotherapy overall.
The drug also reduced the activation of fibroblasts in the tumor microenvironment, providing evidence in patients that supported earlier findings from Salk laboratory studies. Although the trial was not designed to determine whether the treatment improved pancreatic cancer outcomes, researchers observed encouraging signals. Patients who received paricalcitol with chemotherapy had more responses to treatment and were more likely to remain free of disease progression after one year.
Those whose tumors had high levels of the vitamin D receptor and who received paricalcitol also had the longest overall survival. "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 Vitamin D Research Led to a Cancer Trial Evans discovered the nuclear receptor superfamily, a major class of molecules that includes the vitamin D receptor.
Nuclear receptors respond to substances such as hormones, vitamins, and lipids, then influence cell behavior by switching genes "on" and "off." About 13% of all FDA approved drugs currently work by targeting nuclear receptors. Earlier research by Evans and his colleagues also showed that the vitamin D receptor helps regulate fibroblasts in the liver and pancreas in preclinical models. Fibroblasts are connective tissue cells that can contribute to the dense protective structure surrounding pancreatic tumors and some other cancers.
Those studies found particularly high levels of the vitamin D receptor in rare groups of fibroblasts that live within tissues. The receptor also appeared to play an important role in maintaining normal tissue health and stability. The Salk researchers further showed that synthetic forms of vitamin D, including paricalcitol, could block liver fibrosis and pancreatitis in experimental models.
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