title: Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy.
abstract: Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer.
authors.affiliation: Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Hulin-Curtis
authors.affiliation: Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: H
authors.initials: H
authors.lastname: Uusi-Kerttula
authors.affiliation: Velindre Cancer Centre, Cardiff, UK.
authors.forename: R
authors.initials: R
authors.lastname: Jones
authors.affiliation: Velindre Cancer Centre, Cardiff, UK.
authors.forename: L
authors.initials: L
authors.lastname: Hanna
authors.affiliation: Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK.|Velindre Cancer Centre, Cardiff, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Chester
authors.affiliation: Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Parker
mesh_terms: D000072283:A549 Cells; D000256:Adenoviridae / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051916:Membrane Cofactor Protein / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000628:therapy*; D014161:Transduction, Genetic
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein