Breaking Down Barriers: SU2C-Funded Study Identifies Potential New Approach to Treating Pancreatic Cancer

Vitamin D-like drug may make existing treatments for pancreatic cancer more effective.

Researchers may have identified a way of overcoming one of pancreatic cancer’s most formidable defenses, results from a new study suggest. Conducted with funding from Stand Up To Cancer (SU2C), the study found that a drug called paricalcitol may substantially alter the immediate surroundings of pancreatic tumors, potentially making it easier for cancer drugs and immune cells to attack them.

Led by Brian Wolpin, MD, MPH, Kimberly Perez, MD, of Dana-Farber Cancer Institute (DFCI) in Boston, MA, the clinical trial focused on whether adding paricalcitol to the standard treatment for advanced pancreatic cancer, the chemotherapy drugs gemcitabine and nab-paclitaxel, was safe for patients. As they reported in Nature Cancer, no serious side effects were seen in trial participants who received the pill form of paricalcitol or the liquid form (given via an IV). Andressa Dias Costa, MD, of DFCI, and Jonathan Nowak, MD, PhD, of DFCI and Brigham and Women’s Hospital, also helped lead the study.

Importantly, the results also seemed to confirm what the researchers had hoped to see: paricalcitol may be able to disarm fibroblasts, spindle-shaped cells that are critical components of pancreatic tumors’ protective “microenvironment.”

Finally, although the trial wasn’t designed to provide definitive evidence that combining paricalcitol with chemotherapy is more effective than chemotherapy alone, more trial participants who received the combination had reductions in the size of their tumors than those who only got chemotherapy.

The results are preliminary and more research is needed before the approach is ready to be put to the test in a larger clinical trial, Dr. Wolpin and his colleagues cautioned. But, overall, the findings have left them feeling hopeful that they’re on to something.

“I do find these results to be encouraging,” Dr. Perez said. Although there are no immediate plans to test this combination in a larger trial, she continued, the study’s findings lay the groundwork for clinical trials investigating paricalcitol with other treatments, including immunotherapies.

Slowing down fibroblasts

Pancreatic cancer is among the most notorious cancers—and for good reasons. Only a small percentage of people diagnosed with the disease live for more than a few years. In the United States, in fact, despite not being among the 10 most common cancers, it’s the third leading cause of death from cancer.

One reason for these grim statistics is a unique and troublesome feature of pancreatic tumors: they’re often surrounded by a dense, scar tissue-like thicket that, among other things, acts like a blockade to cancer drugs and immune cells. Fibroblasts are among the most problematic components of this barrier-like environment, directly involved in everything from redirecting immune cells to helping tumors grow and spread.

Earlier studies led by another member of the study team, Ronald Evans, PhD, of the Salk Institute for Biological Sciences in San Diego, revealed that these fibroblasts often have large amounts of the vitamin D receptor in their nucleus. This receptor’s job is to latch on to any vitamin D that enters cells from the circulation.

Paricalcitol is a near chemical copycat (or analog) of vitamin D that, just like the real McCoy, can turn on the vitamin D receptor. That activation, these same studies found, causes fibroblasts to become sluggish and decreases inflammation.

Dr. Wolpin and several other researchers had already shown that combining paricalcitol with just gemcitabine was safe in patients with pancreatic cancer. A trial that added nab-paclitaxel was the logical next step, Dr. Perez explained.

Potential to improve pancreatic cancer treatment?

In terms of safety, some patients in the trial who received a high dose of paricalcitol in pill form had significant drops in their calcium levels, although that was quickly remedied by lowering the dose. Otherwise, using the three drugs together was safe.

Tumors shrank in a few trial participants who only received the two chemotherapy drugs. But most people in the study whose tumors shrank also received paricalcitol, including some whose tumors were held in check for many months.

As part of the study, the researchers obtained samples of patients’ tumors before they started treatment and during the treatment. Among patients treated with paricalcitol, those whose tumors had more vitamin D receptors prior to starting treatment were much more likely to have tumor shrinkage. In addition, patients who received paricalcitol were more likely to have cancer-killing immune cells in tumor samples that were collected during treatment.

The findings provide strong evidence that the researchers can achieve their ultimate goal, Dr. Evans said. “By using vitamin D analogs to engage the body’s own natural system for dampening” fibroblast activity in the environment around pancreatic tumors, he said in a press release, “we can enable other [cancer] therapies to do their job.”