Gregg L. Semenza, MD, PhD; Peter J. Ratcliffe, MD; and William G. Kaelin Jr., MD, will share the 2016 Albert Lasker Basic Medical Research Award. Bestowed by the Lasker Foundation, the award recognizes their discovery of the pathway that cells use to sense and adapt to changes in availability of oxygen. Such changes can play a role in cancer progression and the development of other medical conditions.

The Albert and Mary Lasker Foundation honored three distinguished physician–scientists with a coveted award for their independent, groundbreaking research that led to the discovery of HIF1 and explained how the protein drives physiologic changes in response to hypoxia. Such changes can play a role in cancer progression and the development of other medical conditions.

Gregg L. Semenza, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, MD; Peter J. Ratcliffe, MD, of the University of Oxford and the Francis Crick Institute in the UK; and William G. Kaelin Jr., MD, of Dana-Farber Cancer Institute in Boston, MA, will share the 2016 Albert Lasker Basic Medical Research Award and the $250,000 honorarium it carries. The prize was bestowed during a September 23 ceremony in New York, NY.

In the early 1990s, Semenza was trying to explain how hypoxia triggers the production of erythropoietin, promoting the formation of red blood cells, which carry oxygen. Through a series of experiments, he hit upon a nuclear protein that he dubbed HIF1 (composed of HIF1α and HIF1β), which interacts with a particular DNA sequence when cells lack oxygen. However, HIF1, he found, does more than regulate erythropoietin: HIF1 induces VEGF, which plays a role in angiogenesis during tumor formation and development.

Although erythropoietin is produced mainly by kidney and liver cells, Ratcliffe found that HIF1 activates genes in an oxygen-dependent manner in a variety of cell types. He also demonstrated that HIF1 regulates the rate of glycolysis. These findings indicate that HIF1 is part of a universal cellular system that responds to hypoxia.

Kaelin was studying kidney tumors associated with a familial cancer syndrome called von Hippel-Lindau (VHL) disease, characterized by tumors that are rich in newly formed blood vessels. He found that cells lacking VHL protein ramped up erythropoietin production and generated high levels of VEGF even when oxygen levels were high.

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William Kaelin, Peter Ratcliffe, and Gregg Semenza (from left to right) at the Lasker Awards ceremony in September.

Intact VHL, Ratcliffe and Kaelin found, is required for HIF1α degradation under high-oxygen conditions: Prolyl hydroxylases add a hydroxyl group to HIF1α, making it recognizable to VHL, part of a ubiquitin ligase. But because prolyl hydroxylases require oxygen to complete their task, HIF1α remains functional under hypoxia, traveling to a cell's nucleus and activating genes that set off a chain of signals that sustains tumors.

By better understanding the biology of HIF and how cells adapt to the availability of oxygen, these studies helped lay the foundation for developing VEGF inhibitors to decrease the formation of blood vessels that feed cancer, said Kaelin. These drugs include bevacizumab (Avastin; Genentech) and pazopanib (Votrient; GlaxoSmithKline). He noted that HIF inhibitors, which could be an option for patients who don't respond to standard therapies, are under development.

“The goal of the Lasker Awards is not only to celebrate these great scientists,” said Lasker Foundation President Claire Pomeroy, “but also to draw public attention to the importance of sustained investment and societal commitment to medical research.” –Suzanne Rose

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©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.