TY - CHAP
T1 - Therapeutic strategies to block the hypoxic response
AU - DiGiacomo, Josh W.
AU - Gilkes, Daniele M.
N1 - Publisher Copyright:
© Springer Nature Switzerland AG 2019.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019
Y1 - 2019
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
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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 -