Targeting Renal Cell Carcinoma with a HIF-2 antagonist.. Homo sapiens

The most common type of renal cancer, clear-cell Renal Cell Carcinoma (ccRCC), is characterized by VHL inactivation. Because no other gene is mutated as frequently, and VHL mutations are an initiating event, VHL inactivation is regarded as the governing event. VHL loss activates HIF-2, which restores tumor development in VHL-reconstituted ccRCC cell lines. HIF-2, an obligatory heterodimer, promotes cell survival, proliferation, pluripotency, and angiogenesis. Only angiogenesis is targeted clinically today. Angiogenesis inhibitors illustrate the power and limitations of current approaches; FDA-approved drugs like sunitinib uniformly inhibit their targets but all such drugs target either kinases or VEGF. Arguably, the most compelling target is HIF-2. However, HIF-2, a transcription factor, is considered undruggable. Here, we show that a first-in-class HIF-2 inhibitor (PT2399) selectively dissociates HIF-2 complexes in ccRCC, suppressing tumorigenesis in 56% of ccRCC tumorgraft (TG/PDX)lines (10/18).