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Therapeutic Strategies to Block the Hypoxic Response

  • Josh W. DiGiacomo
  • Daniele M. GilkesEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1136)

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.

Keywords

HIF targeting Hypoxia targeting Hypoxia-activated prodrugs 

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Breast and Ovarian Cancer Program, Department of OncologyThe Johns Hopkins School of MedicineBaltimoreUSA
  2. 2.Department of Chemical and Biomolecular EngineeringJohns Hopkins UniversityBaltimoreUSA

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