Therapeutic strategies to block the hypoxic response

Josh W. DiGiacomo, Daniele 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 - Jan 1 2019

Publication series

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

Fingerprint

Prodrugs
Dimerization
DNA
Cytotoxins
Biomarkers
Transcription
Tumors
Therapeutics
Ubiquitination
DNA Damage
Hypoxia
Proteins
Clinical Trials
Neoplasm Metastasis
Neoplasms

Keywords

  • HIF targeting
  • Hypoxia targeting
  • Hypoxia-activated prodrugs

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

DiGiacomo, J. W., & Gilkes, D. (2019). Therapeutic strategies to block the hypoxic response. In Advances in Experimental Medicine and Biology (pp. 141-157). (Advances in Experimental Medicine and Biology; Vol. 1136). Springer New York LLC. https://doi.org/10.1007/978-3-030-12734-3_10

Therapeutic strategies to block the hypoxic response. / DiGiacomo, Josh W.; Gilkes, Daniele.

Advances in Experimental Medicine and Biology. Springer New York LLC, 2019. p. 141-157 (Advances in Experimental Medicine and Biology; Vol. 1136).

Research output: Chapter in Book/Report/Conference proceedingChapter

DiGiacomo, JW & Gilkes, D 2019, Therapeutic strategies to block the hypoxic response. in Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology, vol. 1136, Springer New York LLC, pp. 141-157. https://doi.org/10.1007/978-3-030-12734-3_10
DiGiacomo JW, Gilkes D. Therapeutic strategies to block the hypoxic response. In Advances in Experimental Medicine and Biology. Springer New York LLC. 2019. p. 141-157. (Advances in Experimental Medicine and Biology). https://doi.org/10.1007/978-3-030-12734-3_10
DiGiacomo, Josh W. ; Gilkes, Daniele. / Therapeutic strategies to block the hypoxic response. Advances in Experimental Medicine and Biology. Springer New York LLC, 2019. pp. 141-157 (Advances in Experimental Medicine and Biology).
@inbook{1f681407a092435dbef174868fc54fe8,
title = "Therapeutic strategies to block the hypoxic response",
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{\^A} 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",
author = "DiGiacomo, {Josh W.} and Daniele Gilkes",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/978-3-030-12734-3_10",
language = "English (US)",
series = "Advances in Experimental Medicine and Biology",
publisher = "Springer New York LLC",
pages = "141--157",
booktitle = "Advances in Experimental Medicine and Biology",

}

TY - CHAP

T1 - Therapeutic strategies to block the hypoxic response

AU - DiGiacomo, Josh W.

AU - Gilkes, Daniele

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - HIF targeting

KW - Hypoxia targeting

KW - Hypoxia-activated prodrugs

UR - http://www.scopus.com/inward/record.url?scp=85067602982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067602982&partnerID=8YFLogxK

U2 - 10.1007/978-3-030-12734-3_10

DO - 10.1007/978-3-030-12734-3_10

M3 - Chapter

C2 - 31201722

AN - SCOPUS:85067602982

T3 - Advances in Experimental Medicine and Biology

SP - 141

EP - 157

BT - Advances in Experimental Medicine and Biology

PB - Springer New York LLC

ER -