Co-Clinical Evaluation of Synthetic Vitamin D and Chemotherapy in Pancreatic Cancer by Integrated Imaging and Molecular Analyses
Gupta M, Choi H, Karasic T, Furth EE, Shaffer S, Englander S, Pickup S, Clendenin C, Liu F, Cao Q, Song HK, Fan Y, Duda J, Gee JC, Rosen M, O'Dwyer PJ, Zhou R
Cancer research communications · 0 citas
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Vínculos de autores con la industriaSolo mecanismosDatos neutrales que nuestra revisión registró sobre cómo se hizo este estudio. Describen el método, nunca si nos gusta el resultado.
Cómo se estudió
- Diseño
- Ensayo controlado aleatorizado (indexado por PubMed)
- Estudiado en
- Personas, más trabajo en animales o laboratorio
- Resultado principal
- Solo mecanismos
Quién lo pagó
- Financiación
- Financiación independiente
- Gobierno
- National Center for Advancing Translational Sciences
- Gobierno
- NCI NIH HHS
- Gobierno
- National Center for Advancing Translational Sciences (NCATS)
- Autores
- Al menos un autor declara un vínculo económico con la industria
- Subvenciones
- National Center for Advancing Translational Sciences (U24CA231858)
Según 3 financiadores declarados y la declaración de financiación del texto completo.
Publicación
- Publicado
- 2026-08-01 · Cancer Res Commun · vol. 6 · número 8 · págs. 1983–1992
- Editorial
- American Association for Cancer Research
- Citado
- 0 citas · más que el 60% de estudios similares · 0.0× el promedio de su campo
- Referencias
- 40 trabajos
- Acceso
- Acceso abierto (revista) · CC-BY
- Áreas de investigación
- Pancreatic and Hepatic Oncology Research · Cholangiocarcinoma and Gallbladder Cancer Studies · Pancreatitis Pathology and Treatment
- Palabras clave
- pancreatic ductal adenocarcinoma, paricalcitol, calcipotriol, losartan, nivolumab, perioperative chemotherapy, tumor stroma, fibroblast activation protein, epithelial-mesenchymal transition, chemoresistance, dynamic contrast-enhanced MRI, TGF-beta, vitamin D receptor, genetically engineered mouse models
- MeSH
- animals, humans, mice, carcinoma, pancreatic ductal, pancreatic neoplasms, cisplatin, paclitaxel, ergocalciferols, deoxycytidine, antineoplastic combined chemotherapy protocols, magnetic resonance imaging, pilot projects, aged, female, male, gemcitabine
17 autores
- Mamta Gupta🇺🇸University of Pennsylvania
- Hoon Choi🇺🇸University of Pennsylvania
- Thomas Benjamin Karasic🇺🇸Abramson Cancer Center; University of Pennsylvania
- Emma Elizabeth Furth🇺🇸Abramson Cancer Center; University of Pennsylvania
- Sydney M. Shaffer🇺🇸Abramson Cancer Center; University of Pennsylvania
- Sarah Englander🇺🇸University of Pennsylvania
- Stephen Pickup🇺🇸University of Pennsylvania
- Cynthia J. Clendenin🇺🇸Abramson Cancer Center; University of Pennsylvania
- Fang Liu🇺🇸University of Pennsylvania
- Quy Cao🇺🇸University of Pennsylvania
- Hee Kwon Song🇺🇸University of Pennsylvania
- Yong Fan A🇺🇸University of Pennsylvania
- Jeffrey Duda🇺🇸University of Pennsylvania
- James C. Gee🇺🇸University of Pennsylvania
- Mark A. Rosen🇺🇸Abramson Cancer Center; University of Pennsylvania
- Peter James O'Dwyer🇺🇸Abramson Cancer Center; University of Pennsylvania
- Rong Zhou🇺🇸Abramson Cancer Center; University of Pennsylvania
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial (CC BY).
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