The Versatility Of HIFs
Quite a few headlines touting a term called “HIF compound” or “hypoxia-inducible factor compound” have intrigued us here at WEEKLY headquarters. GlaxoSmithKline (London, England), Akebia Therapeutics (Cambridge, MA) and more have HIF-inducing drugs in the pipeline which may prove to be attractive alternatives to Amgen’s (Thousand Oaks, CA) injectable Epogen currently on the market. In earlier stages of research, HIFs are being studied for their connection to tumor growth. How can one compound be versatile enough to affect both anemia and cancer? Without further ado, let’s take a look at the story behind hypoxia-inducible factors.
Term Of The Week: Hypoxia-Inducible Factor
Hypoxia occurs when the amount of oxygen reaching a person’s cells and tissues is inadequate. Hypoxia may be triggered by lower oxygen concentrations at higher altitudes or by disease processes seen in pulmonary disorders, anemia, or circulatory deficiencies.
The low-oxygen environment in hypoxia causes cells to make a protein called hypoxia-inducible factor (HIF). HIF is a transcription factor — a protein that binds to cellular DNA in a defined location and “turns on” specific genes (which then make their intended proteins).
HIF activates genes involved in the production of oxygen-carrying red blood cells and the formation of blood vessels (angiogenesis). Both of these processes assist in increasing oxygen delivery to hypoxic (oxygen-deprived) tissues.
Activating HIF For Anemia
Anemia is the decrease in the total amount of red blood cells in the body, resulting in a lowered ability of the blood to transport oxygen. In healthy people, when the number of red blood cells in circulation drops, the kidney releases a hormone called erythropoietin, which stimulates the bone marrow to produce more red blood cells. In chronic kidney disease (CKD), the kidneys don’t produce adequate amounts of erythropoietin in response to reduced circulating red blood cells, leading to anemia.
Erythropoietin production can be enhanced by increasing the amount of HIF present.
Under normal oxygen conditions, small amounts of HIF are produced, but are quickly degraded though the action of an enzyme called HIF prolyl-hydroxylase (HIF PHD). HIF PHD is inhibited in low-oxygen conditions, enabling HIF levels to increase. Several companies are developing small molecule, orally available drugs to inhibit HIF PHD, facilitating the activation of HIF under normal oxygen levels. HIF PHD inhibitors in clinical development include:
- Akebia’s vadadustat, Phase III clinical development for CKD anemia
- FibroGen’s (San Francisco, CA) roxadustat, Phase III clinical development for CKD anemia
- GlaxoSmithKline’s daprodustat, Phase III clinical development for CKD anemia
Disrupting Angiogenesis In Cancer
HIF is also thought to contribute to the process of angiogenesis — the growth of blood vessels into tumors. Most solid tumors have a hypoxic environment, due to their high cell density and lack of supporting vascular networks. This hypoxic environment causes cancer cells to produce HIF, which in turn activates the secretion of vascular endothelial cell growth factor (VEGF). VEGF triggers angiogenesis, which provides a way for tumors to get oxygen and nutrients, enabling the tumor to continue growing. Angiogenesis also provides a possible route for individual tumor cells to exit the tumor and spread to other parts of the body.
Because of this relationship between HIF, angiogenesis, and cancer, there is considerable interest in developing HIF inhibitors in an attempt to block angiogenesis. The drugs Torisel (Pfizer; New York, NY) and Zortress (Novartis; Basel, Switzerland) stop mTOR, a protein that activates HIF. It is thought that the anti-angiogenesis effects of these mTOR inhibitors are a result of suppressing HIF. Torisel is FDA-approved for the treatment of renal cell cancer; Zortress is FDA-approved for advanced kidney cancer, metastatic pancreatic neuroendocrine tumors, hormone-positive, and HER2-negative breast cancer.
Cocktail Fodder: The HIF Advantage
You may have heard of “altitude training” — the practice of training at high altitudes in order to increase performance, especially in endurance events such as long distance running or cycling. Altitude training works because at elevations higher than about 5,000 feet there are fewer oxygen molecules per volume of air due to reduced atmospheric pressure. Every breath taken at higher elevations delivers less oxygen than it would at lower elevations, creating a slightly hypoxic environment inside the athlete’s cells. This hypoxia increases the levels of HIF, leading to more erythropoietin and subsequent red blood cell production. The enhanced oxygen-carrying capacity lasts for about ten to twenty days after returning to lower elevations, so an athlete who trains at a higher altitude and then competes at sea level will have an advantage over those who complete all of their training at sea level.