Doctors safely added the vitamin D drug paricalcitol to chemotherapy in a small pancreatic cancer trial

The case for paricalcitol began in studies of fibrosis in the liver and pancreas. Ronald Evans, a Salk professor and co-author of the study, discovered the nuclear receptor superfamily, the class of molecules that includes the vitamin D receptor ^[12]. About 13% of FDA-approved drugs work by targeting nuclear receptors ^[13]. In preclinical models, his group found that the vitamin D receptor helps regulate fibroblasts in the liver and pancreas ^[14]. These connective tissue cells help build the dense structure around pancreatic tumours ^[14]. The receptor was especially abundant in rare groups of them ^[15].

Synthetic analogs such as paricalcitol are designed to resist the process that normally breaks vitamin D down. In experimental models they blocked liver fibrosis and pancreatitis ^[16]. Pancreatic cancer produces an especially strong fibrotic response ^[19], so the team tried the analogs in pancreatic cancer models. There the analogs reversed the activation of cancer-associated fibroblasts, and chemotherapy worked better ^[17].

The fibroblast measurement in patients is what connects this trial to that laboratory work. It is a measurement of tissue. Whether patients live longer is a separate question, and the trial was not designed to answer it ^[7]. The thing this doesn't tell you is how large the clinical effects were. Salk's release on the Nature Cancer paper ^[2] calls the trial small ^[1] and does not report the number of patients, the response rates, the one-year progression figures or the survival times. In a small randomised study, a difference in responses can rest on a few patients.

The receptor signal has a second problem. For the receptor to select patients, high-receptor tumours have to do better with paricalcitol than without it ^[9]. If they also do better on chemotherapy alone, the receptor is picking out tumours with a better outlook, and the drug may not be the reason. Dividing a small trial by receptor level and then by treatment arm also leaves few patients in each group. I think the safety and fibroblast results justify a larger randomised trial sized to detect a survival difference, as long as it measures receptor levels in both arms.

Evans described the approach as a way around drug resistance. "This study really takes a novel approach for cracking therapeutic resistance in pancreatic cancer," he said ^[10]. "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," he said ^[11].