L-R: Dr. William Kaelin, Dr. Gregg Semenza and Dr. Peter Ratcliffe

Three researchers in the U.S. and the U.K. are sharing the 2019 Nobel Prize in Medicine or Physiology for their work on how cells adapt to oxygen availability – research that has led to new strategies to treat diseases like cancers and anemia.

The Nobel Assembly at the Karolinska Institutet in Sweden said Monday that it had awarded the prize to Dr. William Kaelin, professor at Harvard Medical School; Dr. Gregg Semenza, professor at Johns Hopkins University; and Dr. Peter Ratcliffe, director of clinical research at London’s Francis Crick Institute.

According to the announcement, the research – highlighted in publications between 1991 and 2001 – established the basis for understanding how oxygen levels affect cellular metabolism and physiological function, as well as the critical role of oxygen sensing in disease. That, in turn, has led to “intensive” efforts to develop new drugs that can work by activating or blocking the oxygen-sensing machinery in disease states like anemia, cancers, stroke, infections, heart attack and wound healing.

The researchers’ work has led to findings that oxygen sensing allows cells to adapt their metabolism to low oxygen levels, such as during intense exercise. Other adaptive processes controlled by oxygen sensing include generation of new blood vessels and red blood cell production, as well as fine tuning of the immune system and other physiological functions.

Although oxygen sensing and its role in bodily functions like control of the respiratory rate has been known for decades, the way that oxygen controls the process by which hypoxia increases levels of the hormone erythropoietin, and thereby leads to a rise in production of red blood cells, had remained a mystery. Semenza, Ratcliffe and Kaelin managed to find the genes, proteins and peptides responsible.

One of these is a protein complex called hypoxia-inducible factor, or HIF. The discovery of HIF and its role has since led to the development of drugs like roxadustat, a Phase III HIF-prolyl hydroxylase inhibitor that San Francisco-based FibroGen is developing with British drugmaker AstraZeneca and Japan’s Astellas Pharma for anemia associated with chronic kidney disease and myelodysplastic syndrome. Other drugs in developing that target HIF include GlaxoSmithKline’s daprodustat, for which GSK submitted a regulatory approval application to Japanese authorities in August for anemia related to chronic kidney disease. In May, Merck & Co. spent $1.1 billion to acquire Peloton Therapeutics, which is developing the HIF-2a inhibitor PT2977. PT2977 is in development for renal cell carcinoma associated with von Hippel-Lindau disease, or VHL, the focus of Kaelin’s research.

The prize last year went to cancer immunotherapy pioneers Tasuku Honjo, of Kyoto University in Japan, and James Allison, of the University of Texas MD Anderson Cancer Center in Houston. Allison’s research, conducted at the University of California Berkeley in the 1990s, discovered that inhibiting the immune checkpoint CTLA-4 enabled T cells to attack cancer cells, while Honjo discovered the similar role played by PD-1 around the same time. Today, several drugs that target PD-1, PD-L1 and CTLA-4 are on the market for treating cancers.

Photo: Nobel Media