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Nature. 2016 Nov 3;539(7627):107-111. doi: 10.1038/nature19795. Epub 2016 Sep 5.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
2
Peloton Therapeutics, Inc., Dallas, Texas 75235, USA.
3
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
5
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

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.

PMID:
27595393
PMCID:
PMC5499381
DOI:
10.1038/nature19795
[Indexed for MEDLINE]
Free PMC Article

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