Reference Detail

Ref Type

Journal Article

PMID

(27595393)

Authors

Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, Carvo I, Signoretti S, Bruick RK, Josey JA, Wallace EM, Kaelin WG

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature	539	7627	2016 11 03	107-111	Nature

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PT2399	PT2399	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PT2399			HIF2A Inhibitor 6	PT2399 is a small molecule that inhibits Hif2-alpha, resulting in decreased downstream signaling and potentially leading to reduced growth of tumors with defective VHL (PMID: 27595393, PMID: 30523118).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 R248W VHL inact mut	clear cell renal cell carcinoma	resistant	PT2399	Preclinical - Cell culture	Actionable	In a preclinical study, TP53 R248W was associated with resistance to PT2399 in VHL-defective clear cell renal cell carcinoma cell lines in culture (PMID: 27595393).	27595393
VHL inact mut	clear cell renal cell carcinoma	conflicting	PT2399	Preclinical - Pdx	Actionable	In a preclinical study, PT2399 had variable impact on tumor growth in clear cell renal cell carcinoma (ccRCC) cell line and patient-derived xenograft (PDX) models with defective VHL, with decreased tumor growth in a VHL-defective ccRCC PDX model and some VHL-defective ccRCC cell line xenograft models, and no tumor suppression in other cell line xenograft models (PMID: 27595393).	27595393