title: Impaired Synthesis of Stromal Components in Response to Minnelide Improves Vascular Function, Drug Delivery, and Survival in Pancreatic Cancer.
abstract: OBJECTIVE
  Pancreatic cancer stromal microenvironment is considered to be the major reason for failure of conventional and targeted therapy for this disease. The desmoplastic stroma, comprising mainly collagen and glycosaminoglycans like hyaluronan (HA), is responsible for compression of vasculature in the tumor resulting in impaired drug delivery and poor prognosis. Minnelide, a water-soluble prodrug of triptolide currently in phase I clinical trial, has been very effective in multiple animal models of pancreatic cancer. However, whether Minnelide will have efficacious delivery into the tumor despite the desmoplastic stroma has not been evaluated before.
  
  
  METHODS
  Patient tumor-derived xenografts (PDX) and spontaneous pancreatic cancer mice were treated with 0.42 and 0.21 mg/kg body weight for 30 days. Stromal components were determined by IHC and ELISA-based assays. Vascular functionality and drug delivery to the tumor were assessed following treatment with Minnelide.
  
  
  RESULTS
  Our current study shows that treatment with Minnelide resulted in reduction of ECM components like HA and collagen in the pancreatic cancer stroma of both the spontaneous KPC mice as well as in patient tumor xenografts. Furthermore, treatment with Minnelide improved functional vasculature in the tumors resulting in four times more functional vessels in the treated animals compared with untreated animals. Consistent with this observation, Minnelide also resulted in increased drug delivery into the tumor compared with untreated animals. Along with this, Minnelide also decreased viability of the stromal cells along with the tumor cells in pancreatic adenocarcinoma.
  
  
  CONCLUSIONS
  In conclusion, these results are extremely promising as they indicate that Minnelide, along with having anticancer effects is also able to deplete stroma in pancreatic tumors, which makes it an effective therapy for pancreatic cancer.
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Shrey
authors.initials: S
authors.lastname: Modi
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Olivia
authors.initials: O
authors.lastname: McGinn
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Xianda
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sundaram
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota. asaluja@umn.edu.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Saluja
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010755:Organophosphates / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010616:Phenanthrenes / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D010755:Organophosphates; D010616:Phenanthrenes; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt