Almost everyone knows that oxygen is fundamental to the survival and well-being of humans. But how do our cells sense and adapt to the change in oxygen levels? The 2019 Nobel Prize for medicine was awarded for the discovery of this answer, which also gives us new clues in solving the mystery of cancer: anti-VEGF therapy.
The prize was awarded jointly to William Kaelin Jr. of Harvard University, Sir Peter Ratcliffe of Oxford University, and Gregg Semenza of John Hopkins University “for their discoveries of how cells sense and adapt to oxygen availability.”
While it has been understood that oxygen is needed to convert food into energy, the understanding of exactly how each individual cell senses and adapts to oxygen has recently been elusive. This new fundamental understanding of how cells interact with oxygen is groundbreaking, as the human body’s oxygen levels constantly vary due to many factors, such as our activities or state of health at any given moment.
This discovery by these three scientists has greatly improved our perspective on the way oxygen affects our bodies at the cellular level, starting with how the hormone erythropoietin (EPO) stimulates the body into creating red blood cells, which are responsible for transporting oxygen in the body.
When there is a decrease in oxygen levels, the body produces more red blood cells. The EPO hormone itself is partly brought into being by the hypoxia-inducing-factor (HIF) proteins.
Normally, the HIF proteins are quickly captured by the VHL protein (pVHL) and degraded in an oxygen-rich condition. But among people who suffer from Von Hippel Lindau syndrome (VHL), a genetic condition that greatly increases the risk of cancer, their pVHL cannot bind with HIF. Furthermore, similar attributes are found in the cancer cells lacking functional VHL genes. These cancer cells express abnormally high levels of hypoxia-regulated genes; when the functional VHL gene is reintroduced, the levels return to normal.
Further studies have revealed that not only does HIF optimize oxygen levels by regulating the expression of the EPO gene, it also regulates the expression of the vascular endothelial growth factor (VEGF), which stimulates the formation of new blood vessels or “angiogenesis”. Many kinds of cancer cells are able to produce their own VEGF to exploit this process, “tricking” the body into growing new blood vessels (angiogenesis) in order to supply oxygen and nutrients to the cancer cells whilst simultaneously allowing them to spread further.
This breakthrough in our understanding of how oxygen is regulated gives rise to a new cancer-fighting strategy: stopping the angiogenesis process. The research for these anti-angiogenesis agents has been fruitful, with more than 10 such molecules approved by the US FDA and has been widely used. These targeted therapies neutralize cancer cells’ ability to acquire more oxygen and nutrients via the angiogenesis process, either by specifically binding itself to VEGFs and blocking them from activating the VEGF receptor, or binding itself to the VEGF receptors and/or other proteins in the pathways and blocking their activity. Alternatively, some angiogenesis inhibitors are immunomodulatory drugs that also have antiangiogenic properties. Basically, these drugs are “switching off” the blood vessel growing process, resulting in slowing or stopping the tumor growth.
Anti-angiogenesis agents are extremely useful in treating many types of cancers during the advanced and/or metastasis phase. For example, bevacizumab (a monoclonal antibody inhibiting VEGF) is approved for use in some types of colorectal cancer, lung cancer, renal cancer, ovarian cancer, and brain cancer. Sunitinib (an oral drug targeting VEGF receptors) is approved for pancreatic cancer, a certain type of renal cancer, and GIST (gastrointestinal stromal cancer). Sorafenib (another oral drug targeting VEGF receptors) is approved for some types of liver and kidney cancers and progressive thyroid cancer. Pazopanib (also an oral drug targeting VEGF receptors via the mechanism of inhibiting tyrosine kinase) is approved for treatment of renal cell carcinoma and soft tissue sarcomas. Everolimus, an mTOR inhibitor commonly used in ER-positive, HER2 negative locally advanced breast cancer, also shows anti-angiogenesis properties and is approved for pancreatic, gastrointestinal, and certain type of lung cancer as well.
The above list goes on and on; the possibilities for anti-angiogenesis drugs are endless. They even have efficacy in other diseases, such as age-related macular degeneration, an eye condition).
This is what makes “discoveries of how cells sense and adapt to oxygen availability” a breakthrough that is entirely worthy of the Nobel Prize for medicine. It is a key that opens the door to many new pathways in the treatment of cancer.