Abstract
Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2α inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2α-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Antineoplastic Agents / therapeutic use*
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Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / pathology
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Carcinoma, Renal Cell / therapy*
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Cell Respiration / drug effects
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Cell Respiration / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Kidney Neoplasms / therapy*
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Molecular Targeted Therapy* / methods
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Molecular Targeted Therapy* / trends
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Oxygen / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Tumor Hypoxia / drug effects
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Tumor Hypoxia / genetics
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
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Vascular Endothelial Growth Factor A / genetics
Substances
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Antineoplastic Agents
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Basic Helix-Loop-Helix Transcription Factors
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1
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Oxygen