Targeting renal cell carcinoma with a HIF-2 antagonist

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Clear cell renal cell carcinoma (ccRCC) is characterized by frequent inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene.
• VHL inactivation leads to the activation of the HIF-2 transcription factor, a key driver of ccRCC tumorigenesis.
• HIF-2 is implicated in angiogenesis and other cancer-promoting processes, but has been considered undruggable.

Purpose of the Study:

• To evaluate PT2399, a novel selective HIF-2 antagonist, in a tumourgraft/patient-derived xenograft model of ccRCC.
• To assess the efficacy of PT2399 compared to sunitinib and to identify potential resistance mechanisms.

Main Methods:

• Utilized a tumourgraft/patient-derived xenograft platform to test PT2399, a structure-based designed HIF-2 antagonist.
• Assessed tumor suppression, drug tolerance, and identified gene expression signatures in sensitive and resistant ccRCC models.
• Analyzed mutations in HIF-2α and HIF-1β to understand resistance mechanisms.

Main Results:

• PT2399 suppressed tumorigenesis in 56% of human ccRCC lines, demonstrating greater activity and better tolerance than sunitinib.
• Some VHL-mutant ccRCCs were resistant to PT2399, despite evidence of HIF-2 inhibition.
• Resistance was associated with specific gene expression patterns and mutations in HIF-2α and HIF-1β that preserved HIF-2 dimers.

Conclusions:

• HIF-2 is a validated therapeutic target in ccRCC, but some ccRCCs are HIF-2 independent.
• PT2399 and its analogue PT2385 show therapeutic potential, with disease control observed in a heavily pretreated patient.
• Biomarker-driven clinical trials are warranted to guide patient selection for HIF-2 targeted therapies.