title: Combining high selectivity of replication via CXCR4 promoter with fiber chimerism for effective adenoviral oncolysis in breast cancer.
abstract: Conditionally replicative adenoviruses (CRAds) represent novel therapeutic agents that have been recently applied in the context of breast cancer therapy. However, deficiencies in the ability of the adenovirus to infect target tumor cells and to specifically replicate within the tumor target represent key deficiencies preventing the realization of the full potential of this therapeutic approach. Minimal expression of the adenovirus serotype 5 (Ad5) receptor CAR (coxsackie and adenovirus receptor) on breast cancer cells represents a major limitation for Ad5-based virotherapy. Genetic fiber chimerism is a method to alter the tropism of Ad5-based CRAds to achieve CAR-independent infectivity of tumor cells. Here, we describe the use of a CRAd with cancer specific transcriptional control of the essential Ad5 E1A gene using the human CXCR4 gene promoter. We further modified the fiber protein of this agent by switching the knob domain with that of the adenovirus serotype 3. The oncolytic activity of this 5/3 fiber-modified CRAd was studied in breast cancer cell lines, primary breast cancer and human liver tissue slices from patients, and in a xenograft breast cancer mouse model. This infectivity enhanced CRAd agent showed improved replication and killing in breast cancer cells in vitro and in vivo with a remarkable specificity profile that was strongly attenuated in nonbreast cancer cells, as well as in normal human breast and liver tissues. In conclusion, utilization of a CRAd that combined infectivity enhancement strategies and transcriptional targeting improved the CRAd-based antineoplastic effects for breast cancer therapy.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Mariam A
authors.initials: MA
authors.lastname: Stoff-Khalili
authors.forename: Angel A
authors.initials: AA
authors.lastname: Rivera
authors.forename: Alexander
authors.initials: A
authors.lastname: Stoff
authors.forename: J
authors.initials: J
authors.lastname: Michael Mathis
authors.forename: Rodney P
authors.initials: RP
authors.lastname: Rocconi
authors.forename: Qiana L
authors.initials: QL
authors.lastname: Matthews
authors.forename: Michael T
authors.initials: MT
authors.lastname: Numnum
authors.forename: Isabell
authors.initials: I
authors.lastname: Herrmann
authors.forename: Peter
authors.initials: P
authors.lastname: Dall
authors.forename: Devin E
authors.initials: DE
authors.lastname: Eckhoff
authors.forename: Joanne T
authors.initials: JT
authors.lastname: Douglas
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Zeng B
authors.initials: ZB
authors.lastname: Zhu
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D002460:Cell Line; D049109:Cell Proliferation; D020405:Dermis / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics*; D015996:Survival Rate; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D017500:Adenovirus E1A Proteins; D012333:RNA, Messenger; D019718:Receptors, CXCR4