The hypoxic inducible stress response as a target for cancer drug discovery.
All solid tumors experience some degree of hypoxia. The response to the stress of hypoxia is mediated in large part by the hypoxia inducible factor-1 (HIF-1) transcription factor that increases the expression of a variety of genes that allow the tumor to survive and grow in the hostile hypoxic environment. Increased tumor HIF-1 has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis. This has lead to the current interest in HIF-1 as a cancer drug target. HIF-1 activity in tumors depends on the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions or through the activation of oncogenes and/or inactivation of tumor-suppressor genes. HIF-1alpha level and HIF-1 activity are regulated by multiple pathways involving transcription, translation, post-translational modification, and the interaction with other transcription factors. A number of agents have been reported to block HIF-1 activity, acting on all of these mechanisms. Not all of the agents have been shown to block tumor HIF-1 activity in vivo. Some have shown marked HIF-1 inhibition and anti-tumor activity. There are agents already, or soon to be, tested in the clinic as anti-tumor inhibitors of HIF-1. The challenges will be to determine whether the effects of these agents that are seen is due to HIF-1 inhibition and to identify which patients are most likely to benefit from treatment with HIF-1 inhibitors.
Welsh
Sarah J
SJ
Oxford Medical School, University of Oxford, Oxford, UK.
Koh
Mei Yee
MY
Powis
Garth
G
D000951:Antigens, Neoplasm / Q000378:metabolism*; D015507:Drugs, Investigational / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D015507:Drugs, Investigational; D051793:Hypoxia-Inducible Factor 1; D009419:Nerve Tissue Proteins; D017411:Ribonucleoproteins, Small Nuclear; C431323:SART1 protein, human; D016159:Tumor Suppressor Protein p53