title: Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors.
abstract: Hypoxia plays a critical role in driving tumor malignancy and is associated with poor patient survival in many human cancers. Novel therapies targeting hypoxic tumor cells are urgently needed, because these cells hinder tumor eradication. Here we demonstrate than an anticancer strategy based on intratumoral delivery of a novel type of oncolytic adenovirus targeting tumor hypoxia is therapeutically efficient and can augment standard chemotherapy. We used a conditionally replicative adenovirus (HYPR-Ad) to specifically kill hypoxic tumor cells. Viral infection and conditional replication occurred efficiently in hypoxic/hypoxia-inducible factor-active cells in culture and in vivo, prevented tumor formation, and reduced the growth of established tumors. Combining HYPR-Ad with chemotherapy effective against normoxic cells resulted in strongly enhanced antitumor efficacy. These studies demonstrate that targeting the hypoxic microenvironment of tumors rather than an intrinsic gene expression defect is a viable and novel antitumor therapeutic strategy that can be used in combination with existing treatment regimens. The replication and oncolytic potential of this virus was made dependent on hypoxic/hypoxia-inducible factor, a transcription factor activated in the tumor hypoxic microenvironment, broadening its therapeutic use to solid tumors of any genetic make-up or tissue of origin.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Post
authors.forename: Narra Sarojini
authors.initials: NS
authors.lastname: Devi
authors.forename: Zhenchao
authors.initials: Z
authors.lastname: Li
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Ainsley
authors.initials: A
authors.lastname: Nicholson
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D002330:Carmustine / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000235:genetics*; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D002330:Carmustine