Co-Clinical Evaluation of Synthetic Vitamin D and Chemotherapy in Pancreatic Cancer by Integrated Imaging and Molecular Analyses

Purpose: A pilot clinical trial (NCT03519308) was conducted to evaluate perioperative chemotherapy (nab-paclitaxel, gemcitabine, and cisplatin; NGC) plus nivolumab, with or without synthetic vitamin D (paricalcitol) in resectable pancreatic ductal adenocarcinoma (PDAC). Preclinical studies were designed with statistical power to match the clinical trial treatment and compare NGC only versus NGC plus synthetic vitamin D (calcipotriol) or losartan (an antihypertensive medication). Experimental Design: Molecular subtyping was applied to enroll patients with epithelial subtype PDAC. Genetically engineered PDAC model (KPC mice, N=140) were randomized to NGC only and combined therapies. Multiparametric MRI and molecular profiling were integrated to assess treatment-induced effects on stroma, including capillary perfusion and density, matrix collagen content, fibroblast activation protein (FAP) level and transcriptome changes. Results: The clinical trial had limited enrollment (N=3) but confirmed the safety and feasibility of weekly paricalcitol infusion in combination with multiagent chemotherapy. NGC chemotherapy had a profound impact on stroma, inducing a remarkable reduction in FAP level accompanied by a significant increase in matrix collagen content; chemotherapy also activated epithelial mesenchymal transition and reduced blood perfusion and capillary density significantly, resulting in features of chemoresistance. Combining NGC with stromal-targeting agents—Calcipotriol or Losartan— diminished epithelial-to-mesenchymal transition and partially restored perfusion through distinct mechanisms: Calcipotriol activates vitamin D receptor to reprise a quiescent stroma while Losartan suppresses TGFβ to increase lymphocyte infiltration. Conclusion: These findings support further investigations of stromal-directed combination strategies to overcome chemotherapy-induced resistance of PDAC. DCE-MRI may provide a valuable platform to monitor stromal adaptations to therapy in vivo.