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Updated: Mar 15, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models
Hyejin Cho1, Xinlin Du2, James P Rizzi2
1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, 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.
Insights
A novel drug targeting HIF-2α (also known as EPAS1) effectively reduced clear cell renal cell carcinoma tumors in mice. Further research is needed to identify biomarkers for patient selection for this promising cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer.
- ccRCC is often associated with the inactivation of the pVHL tumor suppressor protein.
- Inactivated pVHL leads to the accumulation of the HIF-2α transcription factor.
Purpose of the Study:
- To investigate the therapeutic potential of directly inhibiting HIF-2α in pVHL-defective ccRCC.
- To evaluate the efficacy of the small molecule PT2399 in preclinical models of ccRCC.
Main Methods:
- Utilized preclinical mouse models of primary and metastatic pVHL-defective ccRCC.
- Administered the small molecule inhibitor PT2399, which directly targets HIF-2α.
- Assessed tumor regression and on-target effects of PT2399 treatment.
Main Results:
- Direct inhibition of HIF-2α by PT2399 resulted in significant tumor regression.
- The anti-tumor effect was observed in both primary and metastatic pVHL-defective ccRCC models.
- Sensitivity to PT2399 varied among different ccRCC cell lines.
Conclusions:
- Direct HIF-2α inhibition is a viable therapeutic strategy for pVHL-defective ccRCC.
- The development of predictive biomarkers is crucial for optimizing PT2399 clinical application.
- Targeting HIF-2α offers a promising avenue for ccRCC treatment.
