Therapeutic strategies to block the hypoxic response

Josh W. DiGiacomo, Daniele M. Gilkes

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Patients with the low levels of O2 (hypoxia) in their primary tumors have a higher risk for metastasis and death, indicating a need to therapeutically inhibit the effectors of hypoxia. Many strategies have been developed and investigated to block the hypoxic response. For example, inhibitors of HIF-1 and HIF-2 function by altering the transcription, translation, dimerization, nuclear translocation, DNA-binding, or ubiquitination of the HIF proteins. Hypoxia-activated prodrugs inhibit the hypoxic response through hypoxia-mediated reduction of an inactive, or minimally active, chemical to a cytotoxic agent. Most hypoxia-activated prodrugs function by inducing DNA damage, but others with more novel functions, including prodrugs that release EGFR/HER2 inhibitors also exist. Despite the existence of many therapeutics to combat the hypoxic response, there has been very little success in late phase clinical trials, potentially due to a lack of biomarkers that can be used to stratify patients who would benefit from a hypoxia-targeted therapy.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer New York LLC
Pages141-157
Number of pages17
DOIs
StatePublished - 2019

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1136
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • HIF targeting
  • Hypoxia targeting
  • Hypoxia-activated prodrugs

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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