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 Cancerincluded 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. These compounds are designed to resist the natural process that normally breaks down vitamin D.
Reprogramming the Environment Around Pancreatic Tumors
Pancreatic cancer is known for producing an especially strong fibrotic response, so Evans and his team investigated whether vitamin D analogs could change the environment surrounding pancreatic tumors.
The results surprised them. In pancreatic cancer models, vitamin D analogs were able to reverse the activation of cancer associated fibroblasts. That change was accompanied by stronger responses to chemotherapy.
The work helped establish a different way of thinking about pancreatic cancer treatment. Rather than focusing only on killing cancer cells directly, researchers could try to reprogram the surrounding tissue that supports and protects the tumor.
Testing the Strategy in Patients
Building on the Salk findings, Brian Wolpin, MD, MPH, and Kimberly Perez, MD, at Dana Farber Cancer Institute worked with the Evans team to lead a randomized clinical study focused primarily on safety.
The trial enrolled 36 people with previously untreated metastatic pancreatic cancer. Participants received standard chemotherapy (gemcitabine plus nab-paclitaxel) together with either a placebo, intravenous paricalcitol, or oral paricalcitol.
Paricalcitol is already approved by the FDA to prevent and treat secondary hyperparathyroidism in people with chronic kidney disease.
The primary purpose of the study was to determine whether adding paricalcitol to chemotherapy was safe. Overall, the combination was safely administered. However, five of the 12 patients who received oral paricalcitol developed elevated levels of calcium in their blood. Researchers were able to manage this side effect using standard reductions in dosage.
Vitamin D Analog Alters Tumor Supporting Cells
Another major goal was to determine whether paricalcitol actually produced measurable changes inside the tumors.
Researchers collected biopsies when patients entered the study and again after four to six weeks of treatment. They then used advanced multiplex immunofluorescence and spatial transcriptomic techniques to examine changes in cancer cells and other cells within the tumor environment.
Paricalcitol reduced the activation of fibroblasts inside the tumors (but not their overall numbers). It also increased the infiltration of T cells, immune cells that are typically prevented from entering pancreatic tumors.
These results supported the idea that paricalcitol can remodel the tumor microenvironment, potentially making conditions around the cancer less protective.
Encouraging Treatment Signals in a Small Trial
The study was not designed to compare the effectiveness of the treatments or determine whether paricalcitol extends survival. Even so, researchers observed notable differences between the groups.
Among the 24 patients who received paricalcitol, 10 had a partial response to treatment, equal to 42%. Only one of the 12 patients receiving placebo had a partial response, equal to 9%.
Five patients in the paricalcitol groups also remained free of disease progression at the one year mark. None of the patients in the placebo group did.
Researchers found another potentially important clue when they examined vitamin D receptor levels within the tumors. These levels varied considerably among patients and appeared to be associated with treatment outcomes.
Patients with high vitamin D receptor levels who received paricalcitol responded better to chemotherapy and had the longest overall survival following treatment.
Why Pancreatic Cancer Is So Difficult to Treat
Pancreatic cancer remains among the most challenging cancers to treat successfully. Chemotherapy can slow the disease in some people, but outcomes remain poor, and the environment surrounding the tumor is thought to play an important role in treatment resistance.
Pancreatic tumors are often wrapped in dense connective tissue rich in fibroblasts. This tissue can form a physical barrier that makes it harder for cancer drugs to reach tumor cells. It can also create an immunosuppressive environment that limits the ability of the immune system to attack the cancer.
By altering this protective environment rather than targeting only the cancer cells themselves, vitamin D analogs could offer a way to make other therapies more effective.
Larger Pancreatic Cancer Trials Are Needed
The researchers say these results provide a foundation for larger clinical trials that can directly test whether combining vitamin D analogs with chemotherapy or other cancer treatments improves survival.
Future studies will also need to determine whether the amount of vitamin D receptor present in a tumor before treatment can reliably predict which patients are most likely to benefit from therapies involving vitamin D analogs.
“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.”
Source: www.sciencedaily.com
