Nobel Prize winning research prompts new cancer treatments

Three scientists have jointly been awarded the 2019 Nobel Prize in Physiology or Medicine for their discoveries around cells’ response to oxygen availability. Their revelations have changed biology textbooks, but what are the implications for new pharmaceutical treatments? GlobalData’s Pharmaceutical Technology writer Chris Lo investigates.

Lo says: “In October, the Nobel Assembly at Karolinska Institutet in Sweden announced that William G. Kaelin Jr (Harvard University), Sir Peter Ratcliffe (Oxford University) and Gregg L. Semenza (Johns Hopkins University) had been jointly awarded the 2019 Nobel Prize in Physiology or Medicine.

“The three academics won the prize ‘for their discoveries of how cells interact and adapt to oxygen availability’. The award recognises decades of investigational work by Kaelin, Ratcliffe and Semenza, and their findings have already underpinned the development of new therapies for conditions like anaemia and cancer.

“The work of Semenza, Kaelin and Ratcliffe – in various capacities and at various stages – put together the remaining puzzle pieces to get a clearer picture of how blood O2 levels control the cellular response. The starting point was a hormone called erythropoietin (EPO), the release of which stimulates increased production of red blood cells in response to low oxygen levels (hypoxia).

“EPO’s role as a hormonal reaction to hypoxia has been known since the early 20th century, but separate studies by Semenza and Ratcliffe went deeper, discovering that specific DNA segments located next to the EPO gene mediate the response to hypoxia. They also found that this oxygen-sensing capability is not limited to the kidney cells that normally produce EPO; it is present in many different cells types across virtually all tissues in the body.

“Meanwhile, research into an inherited disorder called von Hippel-Lindau’s (VHL) disease being undertaken by Kaelin at the Dana-Farber Cancer Institute shed more light on the process. Kaelin’s work demonstrated that the VHL gene restored normal levels of hypoxia-regulated genes when introduced to cancer cells, and Ratcliffe’s group confirmed that VHL is required for the degradation of HIF-1α at normal oxygen levels.

“Further investigation by Kaelin and Ratcliffe filled in the final details, identifying the exact protein modification that allows VHL to recognise and bind to HIF-1α to remove it when oxygen levels normalise, with the help of certain oxygen-sensitive enzymes. It was for the discovery of this as yet unknown dance of proteins that led to Semenza, Ratcliffe and Kaelin being awarded this year’s Nobel Prize, after decades of research.

“One of the most obvious applications for drugs targeting cells’ oxygen-sensing mechanism is in anaemia, which is caused by a reduced red blood cell count, impairing the blood’s ability to transport oxygen around the body. Already two potential blockbuster drugs have emerged for the treatment of anaemia caused by chronic kidney disease (CKD).

“Cancer is another disease area in which Ratcliffe, Kaelin and Semenza’s work has already borne fruit in the clinic. Broadly speaking, when cancer cells are hypoxic, they co-opt the body’s oxygen-sensing mechanism to increase oxygen supply and build new nutrition-carrying blood vessels to tumour sites through a process called angiogenesis. This co-opting of the body’s natural defences is what makes some tumours so hard to kill.

Semenza said at the Nobel Prize press conference: “What we’ve learned is that when [cancer cells] become hypoxic, they turn on genes that enable them to invade, metastasise and spread throughout the body. We believe it’s these cells that survive the therapy and come back to kill the patient.”

Partly stemming from the trio’s revelations around oxygen sensing, a wave of angiogenesis inhibitors have been developed to help starve hypoxic tumours when they issue the call for the oxygen they need to survive and grow.