title: Armed and targeted measles virus for chemovirotherapy of pancreatic cancer.
abstract: No curative therapy is currently available for locally advanced or metastatic pancreatic cancer. Therefore, new therapeutic approaches must be considered. Measles virus (MV) vaccine strains have shown promising oncolytic activity against a variety of tumor entities. For specific therapy of pancreatic cancer, we generated a fully retargeted MV that enters cells exclusively through the prostate stem cell antigen (PSCA). Besides a high-membrane frequency on prostate cancer cells, this antigen is expressed on pancreatic adenocarcinoma, but not on non-neoplastic tissue. PSCA expression levels differ within heterogeneous tumor bulks and between human pancreatic cell lines, and we could show specific infection of pancreatic adenocarcinoma cell lines with both high- and low-level PSCA expression. Furthermore, we generated a fully retargeted and armed MV-PNP-anti-PSCA to express the prodrug convertase purine nucleoside phosphorylase (PNP). PNP, which activates the prodrug fludarabine effectively, enhanced the oncolytic efficacy of the virus on infected and bystander cells. Beneficial therapeutic effects were shown in a pancreatic cancer xenograft model. Moreover, in the treatment of gemcitabine-resistant pancreatic adenocarcinoma cells, no cross-resistance to both MV oncolysis and activated prodrug was detected.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bossow
authors.forename: C
authors.initials: C
authors.lastname: Grossardt
authors.forename: A
authors.initials: A
authors.lastname: Temme
authors.forename: M F
authors.initials: MF
authors.lastname: Leber
authors.forename: S
authors.initials: S
authors.lastname: Sawall
authors.forename: E P
authors.initials: EP
authors.lastname: Rieber
authors.forename: R
authors.initials: R
authors.lastname: Cattaneo
authors.forename: C
authors.initials: C
authors.lastname: von Kalle
authors.forename: G
authors.initials: G
authors.lastname: Ungerechts
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000628:therapy* / Q000821:virology; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003131:Combined Modality Therapy; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008459:Measles virus / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy* / Q000821:virology; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D011355:Prodrugs; D011683:Purine-Nucleoside Phosphorylase; D014740:Vidarabine; C024352:fludarabine