Hypoxia-inducible factors (HIFs) are master regulators of gene expression that play a central role in the cell’s adaptation to oxygen starvation. They’re also highly activated in a variety of tumors, which typically have hypoxic microenvironments, and experimental cancer drugs targeting HIF—particularly HIF-2α—are well along in clinical development. Ludwig Oxford’s Tammie Bishop and Peter Ratcliffe explored how one HIF-2α-inhibitor affects ordinary physiological responses to low oxygen. They reported in a Journal of Clinical Investigation paper in January that the inhibitor PT2385 significantly compromises the hypoxic ventilatory response, which normally boosts breathing rate in low oxygen environments. The drug also inhibits the proliferation of cells in carotid bodies, which sense the levels of oxygen and carbon dioxide in the blood and trigger adaptive physiological responses. Their analysis of the biochemistry of these effects suggest they’re induced not by some coincidental effect of PT2385 but directly through its effects on HIF-2α. All this, they argue, suggests a need for caution in using HIF-2 inhibition to treat patients with co-occurring respiratory disorders, or those living at relatively high altitudes.
This article appeared in the August 2020 issue of Ludwig Link. Click here to download a PDF (2 MB).