Abstract
Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
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Biomarkers, Pharmacological
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Carcinoma, Renal Cell / drug therapy*
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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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Cell Line, Tumor
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Disease Models, Animal
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Indans / pharmacology*
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Indans / therapeutic use*
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Kidney Neoplasms / drug therapy*
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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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Mice
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Models, Biological
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Neoplasm Metastasis / drug therapy
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Neoplasm Metastasis / pathology
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Sulfones / pharmacology*
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Sulfones / therapeutic use*
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Transcription, Genetic / drug effects
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
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Xenograft Model Antitumor Assays
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Pharmacological
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Indans
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PT2399
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Sulfones
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endothelial PAS domain-containing protein 1
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, mouse