Research by three doctors provided a basis for tyrosine kinase inhibitors (TKI) and offered advancements in treatment for renal cell carcinoma (RCC) patients. Two such TKIs, sunitinib and sorafenib, remain standard in RCC treatment.
According to a recent announcement by the Kidney Cancer Association, the three recipients awarded the Nobel Prize of 2019 for Physiology are Dr. Kaelin of Dana Farber, Dr. Semenza of Johns Hopkins, and Sir Peter Ratcliffe at Oxford.
The odds of overall survival depend on the size of the cancer and its location. If the tumor is small and has not spread from the kidney to other organs (metastasized), then with surgery the patient has a ninety-three percent chance of up to ten years’ survival.
However, in the event of advanced kidney cancer where the tumor has spread, almost eighty percent of patients will die within twenty-four months.
Mutations in the VHL Gene
Mutations in the VHL gene cause von Hippel Lindau syndrome. The VHL gene overpowers cells and prevents them from dividing or growing uncontrollably. VHL gene mutations may lead to the production of abnormal VHL proteins. Research on these altered genes is critical as it reveals how cells can adapt when oxygen levels change. This process is important in several kidney cancers.
When cells are in need of oxygen, it is called tumor hypoxia. As the tumor grows, its blood supply is no longer adequate.
Dr. Kaelin explains that he focused his initial research on the way in which tumor suppressors lead to kidney cancers. He further explained that knowing how the VHL gene was critically linked to cancers of the kidney was an excellent place to begin his research.
He discovered that an altered VHL gene leads to VHL syndrome, thus increasing the risk of renal cell carcinoma. The resulting tumors mimic tumors that lack oxygen. They send out signals that trigger the production of red blood cells and angiogenesis, which is extra-blood vessel formation.
In the 1990s, Dr. Semenza described hypoxia-inducible factor (HIF) as a key protein that builds up in a low oxygen environment. For example, when cells become hypoxic.
Drs. Ratcliffe and Kaelin each added to Dr. Semenza’s findings showing that VHL proteins target oxygen tags linked to HIF molecules. They destroy HIF when the oxygen is sufficient. They do not destroy HIF when oxygen is scarce.
Professor Christopher Wood at MD Anderson describes the hypoxia pathway, including the loss of VHL proteins and overproduction of HIF, as leading to angiogenesis and production of red blood cells.
Professor Wood credits the three Nobel winners as being responsible for improving patients’ chances for overall survival.
He specifically mentioned Dr. Kaelin and his contributions to a better understanding of cellular hypoxia’s biology and its relationship to HIF and VHL. Professor Wood noted that the novel treatments that will evolve should improve patient outcomes.
During the discussion at the Nobel press conference, Dr. Kaelin spoke highly of his deceased wife who had been a well-known researcher and breast surgeon.