Cancer research communications · 2026
Co-Clinical Evaluation of Synthetic Vitamin D and Chemotherapy in Pancreatic Cancer by Integrated Imaging and Molecular Analyses.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Gupta Mamta, Choi Hoon, Karasic Thomas, Furth Emma E, Shaffer Sydney, Englander Sarah, Pickup Stephen, Clendenin Cynthia, Liu Fang, Cao Quy, Song Hee Kwon, Fan Yong, Duda Jeffrey, Gee James C, Rosen Mark, O'Dwyer Peter J, Zhou Rong
Аннотация
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.
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.