An old diabetes drug finds a new molecular job in pancreatic cancer

The molecular structure of an established medicine can hide abilities outside its original clinical purpose. Investigators used structure-guided computational drug repurposing to identify sitagliptin, a DPP-4 inhibitor normally used for diabetes, as a candidate modulator of ribonucleotide reductase pathways implicated in resistance to gemcitabine. They pursued the idea in cell lines, patient-derived organoids and animal models before treating patients.

The first human study, SITGEM-CARE (NCT05947825), enrolled only 22 evaluable patients with locally advanced or metastatic pancreatic ductal adenocarcinoma. Eight had partial responses (36.4%; 95% CI 17.2%–59.3%), and another 11 had stable disease. Reported median progression-free survival was 6.6 months and median overall survival 12.5 months, with follow-up still limited. There was no concurrent randomized control arm, so none of those outcomes proves that sitagliptin improves on the chemotherapy backbone.

AI helped nominate a molecule and the biology provided a rationale. Neither computational docking nor the early response rate establishes a new effective treatment. The most valuable next experiment would randomize patients to gemcitabine/nab-paclitaxel with or without sitagliptin, measure survival and tolerability, and prespecify target engagement and resistance biomarkers.