On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

Hyejin Cho; Xinlin Du; James P. Rizzi; Ella Liberzon; Abhishek A. Chakraborty; Wenhua Gao; Ingrid Carvo; Sabina Signoretti; Richard K. Bruick; John A. Josey; Eli M. Wallace; William G. Kaelin

doi:10.1038/nature19795

On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

Hyejin Cho, Xinlin Du, James P. Rizzi, Ella Liberzon, Abhishek A. Chakraborty, Wenhua Gao, Ingrid Carvo, Sabina Signoretti, Richard K. Bruick, John A. Josey, Eli M. Wallace, William G. Kaelin

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325 Scopus citations

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.

Original language	English (US)
Pages (from-to)	107-111
Number of pages	5
Journal	Nature
Volume	539
Issue number	7627
DOIs	https://doi.org/10.1038/nature19795
State	Published - 2016

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title = "On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models",

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.",

author = "Hyejin Cho and Xinlin Du and Rizzi, {James P.} and Ella Liberzon and Chakraborty, {Abhishek A.} and Wenhua Gao and Ingrid Carvo and Sabina Signoretti and Bruick, {Richard K.} and Josey, {John A.} and Wallace, {Eli M.} and Kaelin, {William G.}",

year = "2016",

doi = "10.1038/nature19795",

language = "English (US)",

volume = "539",

pages = "107--111",

journal = "Nature",

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T1 - On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

AU - Cho, Hyejin

AU - Du, Xinlin

AU - Rizzi, James P.

AU - Liberzon, Ella

AU - Chakraborty, Abhishek A.

AU - Gao, Wenhua

AU - Carvo, Ingrid

AU - Signoretti, Sabina

AU - Bruick, Richard K.

AU - Josey, John A.

AU - Wallace, Eli M.

AU - Kaelin, William G.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

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On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models

Abstract

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