On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Hyejin
H
Cho
Peloton Therapeutics, Inc., Dallas, Texas 75235, USA.
Xinlin
X
Du
Peloton Therapeutics, Inc., Dallas, Texas 75235, USA.
James P
JP
Rizzi
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Ella
E
Liberzon
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abhishek A
AA
Chakraborty
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Wenhua
W
Gao
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ingrid
I
Carvo
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sabina
S
Signoretti
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Richard K
RK
Bruick
Peloton Therapeutics, Inc., Dallas, Texas 75235, USA.
John A
JA
Josey
Peloton Therapeutics, Inc., Dallas, Texas 75235, USA.
Eli M
EM
Wallace
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
William G
WG
Kaelin
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors*; D054316:Biomarkers, Pharmacological; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D054316:Biomarkers, Pharmacological; D007189:Indans; D013450:Sulfones; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C000614278:PT2399; C494469:VHL protein, mouse