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 experimental regimen and compare NGC only with NGC plus synthetic vitamin D [calcipotriol (Cal)] or losartan (Losa; an antihypertensive medication).

MATERIALS AND

METHODS

Molecular subtyping was applied to enroll patients with epithelial subtype PDAC. Genetically engineered PDAC models (KrasG12D;Trp53R172H;Pdx1-Cre 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) levels 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 levels accompanied by a significant increase in matrix collagen content; chemotherapy also activated epithelial-mesenchymal transition (EMT) and significantly reduced blood perfusion and capillary density, resulting in features of chemoresistance. Combining NGC with stromal-targeting agents-Cal or Losa-diminished EMT and partially restored perfusion through distinct mechanisms: Cal activates the vitamin D receptor to reprise a quiescent stroma, whereas Losa suppresses TGFβ to increase lymphocyte infiltration.

CONCLUSIONS

These findings support further investigations of stromal-directed combination strategies to overcome chemotherapy-induced resistance of PDAC. Dynamic contrast-enhanced MRI may provide a valuable platform to monitor stromal adaptations to therapy in vivo.

SIGNIFICANCE: Results from co-clinical trials integrating MRI and molecular profiling provide a translational rationale for investigating stromal-directed combination strategies in PDAC. These approaches may help preserve chemosensitivity, counteract chemotherapy-induced stromal and vascular remodeling, and overcome adaptive resistance mechanisms that limit durable treatment response.