Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors

Dawn E. Post, Narra Sarojini Devi, Zhenchao Li, Daniel J. Brat, Balveen Kaur, Ainsley Nicholson, Jeffrey J. Olson, Zhaobin Zhang, Erwin G. Van Meir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8603-8612
Number of pages10
JournalClinical Cancer Research
Volume10
Issue number24
DOIs
StatePublished - Dec 15 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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