title: Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models.
abstract: A central resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. Human adenoviruses (Ads) have evolved mechanisms to breach epithelial barriers. For example, during Ad serotype 3 (Ad3) infection of epithelial tumor cells, massive amounts of subviral penton-dodecahedral particles (PtDd) are produced and released from infected cells to trigger the transient opening of epithelial junctions, thus facilitating lateral virus spread. We show here that an Ad3 mutant that is disabled for PtDd production is significantly less effective in killing of epithelial human xenograft tumors than the wild-type Ad3 virus. Intratumoral spread and therapeutic effect of the Ad3 mutant was enhanced by co-administration of a small recombinant protein (JO; produced in Escherichia coli) that incorporated the minimal junction opening domains of PtDd. We then demonstrated that co-administration of JO with replication-competent Ads that do not produce PtDd (Ad5, Ad35) resulted in greater attenuation of tumor growth than virus injection alone. Furthermore, we genetically modified a conditionally replicating Ad5-based oncolytic Ad (Ad5Δ24) to express a secreted form of JO upon replication in tumor cells. The JO-expressing virus had a significantly greater antitumor effect than the unmodified AdΔ24 version. Our findings indicate that epithelial junctions limit the efficacy of oncolytic Ads and that this problem can be address by co-injection or expression of JO. JO has also the potential for improving cancer therapy with other types of oncolytic viruses.
authors.affiliation: 1 Division of Medical Genetics, University of Washington , Seattle, Washington.
authors.forename: Roma
authors.initials: R
authors.lastname: Yumul
authors.affiliation: 1 Division of Medical Genetics, University of Washington , Seattle, Washington.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Richter
authors.affiliation: 1 Division of Medical Genetics, University of Washington , Seattle, Washington.|2 National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention , Beijing, PR China .
authors.forename: Zhuo-Zhuang
authors.initials: ZZ
authors.lastname: Lu
authors.affiliation: 1 Division of Medical Genetics, University of Washington , Seattle, Washington.
authors.forename: Kamola
authors.initials: K
authors.lastname: Saydaminova
authors.affiliation: 1 Division of Medical Genetics, University of Washington , Seattle, Washington.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: 3 BRIM Biotechnology Inc. , Taipei, Taiwan .
authors.forename: Chung-Huei Katherine
authors.initials: CH
authors.lastname: Wang
authors.affiliation: 4 Compliment Corp. , Seattle, Washington.|5 PAI Life Sciences Inc. , Seattle, Washington.
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.affiliation: 1 Division of Medical Genetics, University of Washington , Seattle, Washington.|4 Compliment Corp. , Seattle, Washington.|6 Department of Pathology, University of Washington , Seattle, Washington.
authors.forename: André
authors.initials: A
authors.lastname: Lieber
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D051301:Desmoglein 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051301:Desmoglein 2; C495315:Dsg2 protein, mouse; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins