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.

• Authors: 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
• Journal: Nature (Nature) Vol. 539 Issue 7627 Pg. 107-111 (11 03 2016) ISSN: 1476-4687 [Electronic] England
• PMID: 27595393 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Biomarkers, Pharmacological
• Indans
• PT2399
• Sulfones
• endothelial PAS domain-containing protein 1
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, mouse

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors)
• Biomarkers, Pharmacological
• Carcinoma, Renal Cell (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indans (pharmacology, therapeutic use)
• Kidney Neoplasms (drug therapy, genetics, metabolism, pathology)
• Mice
• Models, Biological
• Neoplasm Metastasis (drug therapy, pathology)
• Sulfones (pharmacology, therapeutic use)
• Transcription, Genetic (drug effects)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays