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A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy

Abstract

New therapy targeting the hypoxic fraction of tumors needs to be designed as this population of cells is the most resistant to radio- and chemotherapies. Hypoxia-inducible factor (HIF) mediates transcriptional responses to hypoxia by binding to hypoxia-responsive elements (HRE) in target genes. We developed a hypoxia/HIF-dependent replicative adenovirus (HYPR-Ad) to target hypoxic cells. HYPR-Ad displays hypoxia-dependent E1A expression and conditional cytolysis of hypoxic but not normoxic cells. This work provides proof-of-principle evidence that an attenuated oncolytic adenovirus that selectively lyses cells under hypoxia can be generated. This therapeutic approach can be used to treat all solid tumors that develop hypoxia, regardless of their tissue origin or genetic alterations.

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Abbreviations

HIF-1:

hypoxia-inducible factor-1

HRE:

hypoxia-responsive elements

HYPR-Ad#1:

hypoxia/HIF-dependent replicative adenovirus

CRAd:

conditionally replicating Ad

CPE:

cytopathic effect

MOI:

multiplicity of infection

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Acknowledgements

We thank Drs L Gooding and A Turnell for generously supplying antibodies and technical advice, members of the Van Meir lab for their helpful discussions, and Drs Dan Brat, Chalet Tan, Leland Chung, Chia-Ling Hsieh, and Lily Yang for a critical reading of the manuscript. This research was supported by NIH Grants CA87830 and NS41403, the C Geyer Foundation and The Brain Tumor Society.

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Correspondence to Erwin G Van Meir.

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Post, D., Van Meir, E. A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Oncogene 22, 2065–2072 (2003). https://doi.org/10.1038/sj.onc.1206464

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Keywords

  • hypoxia
  • adenovirus
  • HIF
  • gene delivery
  • oncolysis
  • tumor

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